947 results on '"Crotty, Shane"'
Search Results
2. Exploring synergies between B- and T-cell vaccine approaches to optimize immune responses against HIV-workshop report.
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Maciel, Milton, Amara, Rama, Bar, Katharine, Crotty, Shane, Deeks, Steven, Duplessis, Christopher, Gaiha, Gaurav, McElrath, M, McMichael, Andrew, Palin, Amy, Rutishauser, Rachel, Shapiro, Stuart, Smiley, Stephen, and DSouza, M
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The US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institute of Health (NIH), convened a virtual workshop on August 8-9th, 2023 to explore potential synergies between HIV vaccine approaches that are designed to induce cellular or humoral immune responses. The goal of this workshop was to review data on leading vaccine candidates and to discuss the best strategies for combining these approaches to optimize immunity against HIV. Here, we summarize the findings reviewed at the workshop and discuss the knowledge gaps and priorities for future studies that will help accelerate the development of a preventive HIV vaccine.
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- 2024
3. Vaccination induces broadly neutralizing antibody precursors to HIV gp41
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Schiffner, Torben, Phung, Ivy, Ray, Rashmi, Irimia, Adriana, Tian, Ming, Swanson, Olivia, Lee, Jeong Hyun, Lee, Chang-Chun D., Marina-Zárate, Ester, Cho, So Yeon, Huang, Jiachen, Ozorowski, Gabriel, Skog, Patrick D., Serra, Andreia M., Rantalainen, Kimmo, Allen, Joel D., Baboo, Sabyasachi, Rodriguez, Oscar L., Himansu, Sunny, Zhou, Jianfu, Hurtado, Jonathan, Flynn, Claudia T., McKenney, Katherine, Havenar-Daughton, Colin, Saha, Swati, Shields, Kaitlyn, Schultze, Steven, Smith, Melissa L., Liang, Chi-Hui, Toy, Laura, Pecetta, Simone, Lin, Ying-Cing, Willis, Jordan R., Sesterhenn, Fabian, Kulp, Daniel W., Hu, Xiaozhen, Cottrell, Christopher A., Zhou, Xiaoya, Ruiz, Jennifer, Wang, Xuesong, Nair, Usha, Kirsch, Kathrin H., Cheng, Hwei-Ling, Davis, Jillian, Kalyuzhniy, Oleksandr, Liguori, Alessia, Diedrich, Jolene K., Ngo, Julia T., Lewis, Vanessa, Phelps, Nicole, Tingle, Ryan D., Spencer, Skye, Georgeson, Erik, Adachi, Yumiko, Kubitz, Michael, Eskandarzadeh, Saman, Elsliger, Marc A., Amara, Rama R., Landais, Elise, Briney, Bryan, Burton, Dennis R., Carnathan, Diane G., Silvestri, Guido, Watson, Corey T., Yates, III, John R., Paulson, James C., Crispin, Max, Grigoryan, Gevorg, Ward, Andrew B., Sok, Devin, Alt, Frederick W., Wilson, Ian A., Batista, Facundo D., Crotty, Shane, and Schief, William R.
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- 2024
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4. Affinity gaps among B cells in germinal centers drive the selection of MPER precursors
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Ray, Rashmi, Schiffner, Torben, Wang, Xuesong, Yan, Yu, Rantalainen, Kimmo, Lee, Chang-Chun David, Parikh, Shivang, Reyes, Raphael A., Dale, Gordon A., Lin, Ying-Cing, Pecetta, Simone, Giguere, Sophie, Swanson, Olivia, Kratochvil, Sven, Melzi, Eleonora, Phung, Ivy, Madungwe, Lisa, Kalyuzhniy, Oleksandr, Warner, John, Weldon, Stephanie R., Tingle, Ryan, Lamperti, Edward, Kirsch, Kathrin H., Phelps, Nicole, Georgeson, Erik, Adachi, Yumiko, Kubitz, Michael, Nair, Usha, Crotty, Shane, Wilson, Ian A., Schief, William R., and Batista, Facundo D.
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- 2024
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5. Priming antibody responses to the fusion peptide in rhesus macaques
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Cottrell, Christopher A., Pratap, Payal P., Cirelli, Kimberly M., Carnathan, Diane G., Enemuo, Chiamaka A., Antanasijevic, Aleksandar, Ozorowski, Gabriel, Sewall, Leigh M., Gao, Hongmei, Allen, Joel D., Nogal, Bartek, Silva, Murillo, Bhiman, Jinal, Pauthner, Matthias, Irvine, Darrell J., Montefiori, David, Crispin, Max, Burton, Dennis R., Silvestri, Guido, Crotty, Shane, and Ward, Andrew B.
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- 2024
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6. Author Correction: Exploring synergies between B- and T-cell vaccine approaches to optimize immune responses against HIV—workshop report
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Maciel, Jr, Milton, Amara, Rama R., Bar, Katharine J., Crotty, Shane, Deeks, Steven G., Duplessis, Christopher, Gaiha, Gaurav, McElrath, M. Juliana, McMichael, Andrew, Palin, Amy, Rutishauser, Rachel, Shapiro, Stuart, Smiley, Stephen T., and D’Souza, M. Patricia
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- 2024
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7. Transcriptional programming of CD4+ TRM differentiation in viral infection balances effector- and memory-associated gene expression
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Nguyen, Quynh P, Takehara, Kennidy K, Deng, Tianda Z, O'Shea, Shannon, Heeg, Maximilian, Omilusik, Kyla D, Milner, J Justin, Quon, Sara, Pipkin, Matthew E, Choi, Jinyong, Crotty, Shane, and Goldrath, Ananda W
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Biomedical and Clinical Sciences ,Immunology ,Genetics ,Prevention ,Infectious Diseases ,HIV/AIDS ,Underpinning research ,1.1 Normal biological development and functioning ,Humans ,Immunologic Memory ,Virus Diseases ,CD4-Positive T-Lymphocytes ,Cell Differentiation ,Gene Expression ,Clinical sciences - Abstract
After resolution of infection, T cells differentiate into long-lived memory cells that recirculate through secondary lymphoid organs or establish residence in tissues. In contrast to CD8+ tissue-resident memory T cells (TRM), the developmental origins and transcriptional regulation of CD4+ TRM remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profiles of CD4+ TRM in the small intestine (SI) responding to acute viral infection, revealing a shared gene expression program and chromatin accessibility profile with circulating TH1 and the progressive acquisition of a mature TRM program. Single-cell RNA sequencing identified heterogeneity among established CD4+ TRM, which were predominantly located in the lamina propria, and revealed a population of cells that coexpressed both effector- and memory-associated genes, including the transcriptional regulators Blimp1, Id2, and Bcl6. TH1-associated Blimp1 and Id2 and TFH-associated Bcl6 were required for early TRM formation and development of a mature TRM population in the SI. These results demonstrate a developmental relationship between TH1 effector cells and the establishment of early TRM, as well as highlighted differences in CD4+ versus CD8+ TRM populations, providing insights into the mechanisms underlying the origins, differentiation, and persistence of CD4+ TRM in response to viral infection.
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- 2023
8. DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells.
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Quon, Sara, Yu, Bingfei, Russ, Brendan, Tsyganov, Kirill, Nguyen, Hongtuyet, Toma, Clara, Heeg, Maximilian, Hocker, James, Milner, J, Crotty, Shane, Pipkin, Matthew, Turner, Stephen, and Goldrath, Ananda
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CD8(+) T cell ,CTCF ,Hi-C ,enhancer ,epigenetics ,genome organization ,promoter ,Humans ,Binding Sites ,CCCTC-Binding Factor ,CD8-Positive T-Lymphocytes ,Chromatin ,DNA ,Protein Binding ,Repressor Proteins - Abstract
Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8+ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8+ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8+ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8+ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.
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- 2023
9. Author Correction: Vaccination induces broadly neutralizing antibody precursors to HIV gp41
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Schiffner, Torben, Phung, Ivy, Ray, Rashmi, Irimia, Adriana, Tian, Ming, Swanson, Olivia, Lee, Jeong Hyun, Lee, Chang-Chun D., Marina-Zárate, Ester, Cho, So Yeon, Huang, Jiachen, Ozorowski, Gabriel, Skog, Patrick D., Serra, Andreia M., Rantalainen, Kimmo, Allen, Joel D., Baboo, Sabyasachi, Rodriguez, Oscar L., Himansu, Sunny, Zhou, Jianfu, Hurtado, Jonathan, Flynn, Claudia T., McKenney, Katherine, Havenar-Daughton, Colin, Saha, Swati, Shields, Kaitlyn, Schultze, Steven, Smith, Melissa L., Liang, Chi-Hui, Toy, Laura, Pecetta, Simone, Lin, Ying-Cing, Willis, Jordan R., Sesterhenn, Fabian, Kulp, Daniel W., Hu, Xiaozhen, Cottrell, Christopher A., Zhou, Xiaoya, Ruiz, Jennifer, Wang, Xuesong, Nair, Usha, Kirsch, Kathrin H., Cheng, Hwei-Ling, Davis, Jillian, Kalyuzhniy, Oleksandr, Liguori, Alessia, Diedrich, Jolene K., Ngo, Julia T., Lewis, Vanessa, Phelps, Nicole, Tingle, Ryan D., Spencer, Skye, Georgeson, Erik, Adachi, Yumiko, Kubitz, Michael, Eskandarzadeh, Saman, Elsliger, Marc A., Amara, Rama R., Landais, Elise, Briney, Bryan, Burton, Dennis R., Carnathan, Diane G., Silvestri, Guido, Watson, Corey T., Yates, III, John R., Paulson, James C., Crispin, Max, Grigoryan, Gevorg, Ward, Andrew B., Sok, Devin, Alt, Frederick W., Wilson, Ian A., Batista, Facundo D., Crotty, Shane, and Schief, William R.
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- 2024
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10. Development of Host Immune Response to Bacteriophage in a Lung Transplant Recipient on Adjunctive Phage Therapy for a Multidrug-Resistant Pneumonia
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Dan, Jennifer M, Lehman, Susan M, Al-kolla, Rita, Penziner, Samuel, Afshar, Kamyar, Yung, Gordon, Golts, Eugene, Law, Nancy, Logan, Cathy, Kovach, Zsuzsanna, Mearns, Gill, Schooley, Robert T, Aslam, Saima, and Crotty, Shane
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Pneumonia & Influenza ,Pneumonia ,Emerging Infectious Diseases ,Biodefense ,Infectious Diseases ,Antimicrobial Resistance ,Lung ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Infection ,Humans ,Bacteriophages ,Phage Therapy ,Transplant Recipients ,Immunity ,Pseudomonas aeruginosa ,Pseudomonas Infections ,AIM ,PBMC ,anti-phage antibody ,bacteriophage ,immune response ,phage therapy ,T follicular helper cell ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Bacteriophage therapy is the use of viruses to kill bacteria for the treatment of antibiotic-resistant infections. Little is known about the human immune response following phage therapy. We report the development of phage-specific CD4 T cells alongside rising phage-specific immunoglobulin G and neutralizing antibodies in response to adjunctive bacteriophage therapy used to treat a multidrug-resistant Pseudomonas aeruginosa pneumonia in a lung transplant recipient. Clinically, treatment was considered a success despite the development phage-specific immune responses.
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- 2023
11. Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients
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Lam, Michael Tun Yin, Duttke, Sascha H, Odish, Mazen F, Le, Hiep D, Hansen, Emily A, Nguyen, Celina T, Trescott, Samantha, Kim, Roy, Deota, Shaunak, Chang, Max W, Patel, Arjun, Hepokoski, Mark, Alotaibi, Mona, Rolfsen, Mark, Perofsky, Katherine, Warden, Anna S, Foley, Jennifer, Ramirez, Sydney I, Dan, Jennifer M, Abbott, Robert K, Crotty, Shane, Alexander, Laura E Crotty, Malhotra, Atul, Panda, Satchidananda, Benner, Christopher W, and Coufal, Nicole G
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Biomedical and Clinical Sciences ,Genetics ,Lung ,Human Genome ,Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Humans ,Transcription Factors ,COVID-19 ,Gene Expression Regulation ,Leukocytes ,Intensive Care Units ,active cistrome ,acute respiratory distress syndrome ,biomarkers ,critical care ,disease stratification ,endotyping ,enhancer RNA ,transcription factor activity ,transcriptional regulation ,Biomedical and clinical sciences - Abstract
Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.
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- 2023
12. Bamlanivimab therapy for acute COVID-19 does not blunt SARS-CoV-2-specific memory T cell responses
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Ramirez, Sydney I, Grifoni, Alba, Weiskopf, Daniela, Parikh, Urvi M, Heaps, Amy, Faraji, Farhoud, Sieg, Scott F, Ritz, Justin, Moser, Carlee, Eron, Joseph J, Currier, Judith S, Klekotka, Paul, Sette, Alessandro, Wohl, David A, Daar, Eric S, Hughes, Michael D, Chew, Kara W, Smith, Davey M, Crotty, Shane, and Team, for the Accelerating COVID-19 Therapeutic Interventions and Vaccines–2 A5401 Study
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Biomedical and Clinical Sciences ,Immunology ,Vaccine Related ,Infectious Diseases ,Clinical Research ,Biodefense ,Emerging Infectious Diseases ,Lung ,Pneumonia ,Pneumonia & Influenza ,Prevention ,Inflammatory and immune system ,Good Health and Well Being ,Humans ,SARS-CoV-2 ,COVID-19 ,Memory T Cells ,Antibodies ,Monoclonal ,Humanized ,Antibodies ,Viral ,Accelerating COVID-19 Therapeutic Interventions and Vaccines–2/A5401 (ACTIV-2/A5401) Study Team ,Adaptive immunity ,Biomedical and clinical sciences ,Health sciences - Abstract
Despite the widespread use of SARS-CoV-2-specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2-specific T cell responses has been unknown, resulting in uncertainty as to whether anti-SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2-specific mAb may enhance adaptive immunity to SARS-CoV-2 via a "vaccinal effect." Bamlanivimab (Eli Lilly and Company) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2-specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with bamlanivimab versus placebo. SARS-CoV-2-specific T cell responses were evaluated using activation-induced marker assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 developed SARS-CoV-2-specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2-specific T cell memory were not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2-specific cellular immunity.
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- 2022
13. Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques
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He, Wan-Ting, Yuan, Meng, Callaghan, Sean, Musharrafieh, Rami, Song, Ge, Silva, Murillo, Beutler, Nathan, Lee, Wen-Hsin, Yong, Peter, Torres, Jonathan L, Melo, Mariane, Zhou, Panpan, Zhao, Fangzhu, Zhu, Xueyong, Peng, Linghang, Huang, Deli, Anzanello, Fabio, Ricketts, James, Parren, Mara, Garcia, Elijah, Ferguson, Melissa, Rinaldi, William, Rawlings, Stephen A, Nemazee, David, Smith, Davey M, Briney, Bryan, Safonova, Yana, Rogers, Thomas F, Dan, Jennifer M, Zhang, Zeli, Weiskopf, Daniela, Sette, Alessandro, Crotty, Shane, Irvine, Darrell J, Ward, Andrew B, Wilson, Ian A, Burton, Dennis R, and Andrabi, Raiees
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Vaccine Related ,Pneumonia & Influenza ,Emerging Infectious Diseases ,Biotechnology ,Biodefense ,Prevention ,Immunization ,Vaccine Related (AIDS) ,Pneumonia ,Lung ,Infectious Diseases ,Infection ,Good Health and Well Being ,Animals ,Antibodies ,Neutralizing ,Antibodies ,Viral ,Broadly Neutralizing Antibodies ,COVID-19 ,Epitopes ,Humans ,Macaca mulatta ,SARS-CoV-2 ,Spike Glycoprotein ,Coronavirus ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - Abstract
To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses to CoVs. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein with a two-shot protocol generated potent serum receptor binding domain cross-neutralizing antibody responses to both SARS-CoV-2 and SARS-CoV-1. Furthermore, responses were equally effective against most SARS-CoV-2 variants of concern (VOCs) and some were highly effective against Omicron. This result contrasts with human infection or many two-shot vaccination protocols where responses were typically more SARS-CoV-2 specific and where VOCs were less well neutralized. Structural studies showed that cloned macaque neutralizing antibodies, particularly using a given heavy chain germline gene, recognized a relatively conserved region proximal to the angiotensin converting enzyme 2 receptor binding site (RBS), whereas many frequently elicited human neutralizing antibodies targeted more variable epitopes overlapping the RBS. B cell repertoire differences between humans and macaques appeared to influence the vaccine response. The macaque neutralizing antibodies identified a pan-SARS-related virus epitope region less well targeted by human antibodies that could be exploited in rational vaccine design.
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- 2022
14. SARS-CoV-2 breakthrough infections enhance T cell response magnitude, breadth, and epitope repertoire
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Tarke, Alison, Ramezani-Rad, Parham, Alves Pereira Neto, Tertuliano, Lee, Yeji, Silva-Moraes, Vanessa, Goodwin, Benjamin, Bloom, Nathaniel, Siddiqui, Leila, Avalos, Liliana, Frazier, April, Zhang, Zeli, da Silva Antunes, Ricardo, Dan, Jennifer, Crotty, Shane, Grifoni, Alba, and Sette, Alessandro
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- 2024
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15. A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates
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Phung, Ivy, Rodrigues, Kristen A., Marina-Zárate, Ester, Maiorino, Laura, Pahar, Bapi, Lee, Wen-Hsin, Melo, Mariane, Kaur, Amitinder, Allers, Carolina, Fahlberg, Marissa, Grasperge, Brooke F., Dufour, Jason P., Schiro, Faith, Aye, Pyone P., Lopez, Paul G., Torres, Jonathan L., Ozorowski, Gabriel, Eskandarzadeh, Saman, Kubitz, Michael, Georgeson, Erik, Groschel, Bettina, Nedellec, Rebecca, Bick, Michael, Kaczmarek Michaels, Katarzyna, Gao, Hongmei, Shen, Xiaoying, Carnathan, Diane G., Silvestri, Guido, Montefiori, David C., Ward, Andrew B., Hangartner, Lars, Veazey, Ronald S., Burton, Dennis R., Schief, William R., Irvine, Darrell J., and Crotty, Shane
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- 2023
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16. Development of a T cell-based immunodiagnostic system to effectively distinguish SARS-CoV-2 infection and COVID-19 vaccination status
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Yu, Esther Dawen, Wang, Eric, Garrigan, Emily, Goodwin, Benjamin, Sutherland, Aaron, Tarke, Alison, Chang, James, Gálvez, Rosa Isela, Mateus, Jose, Ramirez, Sydney I, Rawlings, Stephen A, Smith, Davey M, Filaci, Gilberto, Frazier, April, Weiskopf, Daniela, Dan, Jennifer M, Crotty, Shane, Grifoni, Alba, Sette, Alessandro, and da Silva Antunes, Ricardo
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Vaccine Related ,Immunization ,Biodefense ,Lung ,Infectious Diseases ,Pneumonia & Influenza ,Prevention ,Emerging Infectious Diseases ,3.4 Vaccines ,Prevention of disease and conditions ,and promotion of well-being ,Infection ,Good Health and Well Being ,Antibodies ,Viral ,COVID-19 ,COVID-19 Vaccines ,Epitopes ,T-Lymphocyte ,Humans ,SARS-CoV-2 ,Spike Glycoprotein ,Coronavirus ,Vaccination ,T cells ,breakthrough infection ,epitope ,immunodiagnostic tool ,vaccination ,viruses ,Microbiology ,Medical Microbiology ,Immunology - Abstract
Both SARS-CoV-2 infections and COVID-19 vaccines elicit memory T cell responses. Here, we report the development of 2 pools of experimentally defined SARS-CoV-2 T cell epitopes that, in combination with spike, were used to discriminate 4 groups of subjects with different SARS-CoV-2 infection and COVID-19 vaccine status. The overall T cell-based classification accuracy was 89.2% and 88.5% in the experimental and validation cohorts. This scheme was applicable to different mRNA vaccines and different lengths of time post infection/post vaccination and yielded increased accuracy when compared to serological readouts. T cell responses from breakthrough infections were also studied and effectively segregated from vaccine responses, with a combined performance of 86.6% across all 239 subjects from the 5 groups. We anticipate that a T cell-based immunodiagnostic scheme to classify subjects based on their vaccination and natural infection history will be an important tool for longitudinal monitoring of vaccinations and for establishing SARS-CoV-2 correlates of protection.
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- 2022
17. Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature
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Masso-Silva, Jorge A, Moshensky, Alexander, Lam, Michael TY, Odish, Mazen F, Patel, Arjun, Xu, Le, Hansen, Emily, Trescott, Samantha, Nguyen, Celina, Kim, Roy, Perofsky, Katherine, Perera, Samantha, Ma, Lauren, Pham, Josephine, Rolfsen, Mark, Olay, Jarod, Shin, John, Dan, Jennifer M, Abbott, Robert K, Ramirez, Sydney, Alexander, Thomas H, Lin, Grace Y, Fuentes, Ana Lucia, Advani, Ira, Gunge, Deepti, Pretorius, Victor, Malhotra, Atul, Sun, Xin, Duran, Jason, Hepokoski, Mark, Crotty, Shane, Coufal, Nicole G, Meier, Angela, and Alexander, Laura E Crotty
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Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Infectious Diseases ,Lung ,Aetiology ,2.1 Biological and endogenous factors ,Respiratory ,Good Health and Well Being ,COVID-19 ,Critical Illness ,Extracellular Traps ,Humans ,Neutrophil Activation ,Neutrophils ,Phenotype ,SARS-CoV-2 ,neutrophil ,NETs ,NETosis ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,Clinical sciences - Abstract
BackgroundIncreased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.MethodsBlood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English.ResultsElevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1β, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P
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- 2022
18. Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection
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Milner, J Justin, Toma, Clara, Quon, Sara, Omilusik, Kyla, Scharping, Nicole E, Dey, Anup, Reina-Campos, Miguel, Nguyen, Hongtuyet, Getzler, Adam J, Diao, Huitian, Yu, Bingfei, Delpoux, Arnaud, Yoshida, Tomomi M, Li, Deyao, Qi, Jun, Vincek, Adam, Hedrick, Stephen M, Egawa, Takeshi, Zhou, Ming-Ming, Crotty, Shane, Ozato, Keiko, Pipkin, Matthew E, and Goldrath, Ananda W
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Genetics ,Infectious Diseases ,Emerging Infectious Diseases ,Vaccine Related ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,CD8-Positive T-Lymphocytes ,Cell Differentiation ,Chromatin ,Enhancer Elements ,Genetic ,Mice ,Knockout ,Neoplasms ,Nuclear Proteins ,Protein Binding ,RNA Interference ,Transcription Factors ,Transcription ,Genetic ,Virus Diseases ,Medical and Health Sciences ,Immunology - Abstract
In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule-mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.
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- 2021
19. Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals.
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Tarke, Alison, Sidney, John, Methot, Nils, Yu, Esther Dawen, Zhang, Yun, Dan, Jennifer M, Goodwin, Benjamin, Rubiro, Paul, Sutherland, Aaron, Wang, Eric, Frazier, April, Ramirez, Sydney I, Rawlings, Stephen A, Smith, Davey M, da Silva Antunes, Ricardo, Peters, Bjoern, Scheuermann, Richard H, Weiskopf, Daniela, Crotty, Shane, Grifoni, Alba, and Sette, Alessandro
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CD4 ,CD8 ,COVID-19 ,SARS-CoV-2 ,T cells ,VOCs ,vaccines - Abstract
The emergence of SARS-CoV-2 variants with evidence of antibody escape highlight the importance of addressing whether the total CD4+ and CD8+ T cell recognition is also affected. Here, we compare SARS-CoV-2-specific CD4+ and CD8+ T cells against the B.1.1.7, B.1.351, P.1, and CAL.20C lineages in COVID-19 convalescents and in recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. The total reactivity against SARS-CoV-2 variants is similar in terms of magnitude and frequency of response, with decreases in the 10%-22% range observed in some assay/VOC combinations. A total of 7% and 3% of previously identified CD4+ and CD8+ T cell epitopes, respectively, are affected by mutations in the various VOCs. Thus, the SARS-CoV-2 variants analyzed here do not significantly disrupt the total SARS-CoV-2 T cell reactivity; however, the decreases observed highlight the importance for active monitoring of T cell reactivity in the context of SARS-CoV-2 evolution.
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- 2021
20. AI-guided discovery of the invariant host response to viral pandemics.
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Sahoo, Debashis, Katkar, Gajanan D, Khandelwal, Soni, Behroozikhah, Mahdi, Claire, Amanraj, Castillo, Vanessa, Tindle, Courtney, Fuller, MacKenzie, Taheri, Sahar, Rogers, Thomas F, Beutler, Nathan, Ramirez, Sydney I, Rawlings, Stephen A, Pretorius, Victor, Smith, Davey M, Burton, Dennis R, Alexander, Laura E Crotty, Duran, Jason, Crotty, Shane, Dan, Jennifer M, Das, Soumita, and Ghosh, Pradipta
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Lung ,Animals ,Humans ,Mesocricetus ,Virus Diseases ,Disease Models ,Animal ,Hydroxylamines ,Cytidine ,Genetic Markers ,Interleukin-15 ,Antiviral Agents ,Autopsy ,Gene Expression Profiling ,Artificial Intelligence ,Databases ,Genetic ,Cricetinae ,Receptors ,Interleukin-15 ,Gene Regulatory Networks ,Antibodies ,Neutralizing ,Pandemics ,COVID-19 ,Angiotensin-Converting Enzyme 2 ,Angiotensin converting enzyme (ACE)-2 ,Artificial intelligence/machine learning ,Boolean equivalent clusters ,Coronavirus COVID-19 ,Immune response ,Interleukin 15 ,Lung alveoli ,Natural Killer (NK) cells ,Prevention ,Infectious Diseases ,Biodefense ,Clinical Research ,Emerging Infectious Diseases ,Vaccine Related ,Clinical Sciences ,Public Health and Health Services - Abstract
BackgroundCoronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach.MethodOver 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. An AI-based approach was used to explore the utility of the signature in navigating the uncharted territory of Covid-19, setting therapeutic goals, and finding therapeutic solutions.FindingsThe 166-gene signature was surprisingly conserved across all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determine severity/fatality. Precise therapeutic goals could be formulated; these goals were met in high-dose SARS-CoV-2-challenged hamsters using either neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine prognosticated disease severity.InterpretationThe ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.FundingThis work was supported by the National Institutes for Health (NIH) [grants CA151673 and GM138385 (to DS) and AI141630 (to P.G), DK107585-05S1 (SD) and AI155696 (to P.G, D.S and S.D), U19-AI142742 (to S.C, cchiCooperative Centers for Human Immunology)]; Research Grants Program Office (RGPO) from the University of California Office of the President (UCOP) (R00RG2628 & R00RG2642 to P.G, D.S and S.D); the UC San Diego Sanford Stem Cell Clinical Center (to P.G, D.S and S.D); LJI Institutional Funds (to S.C); the VA San Diego Healthcare System Institutional funds (to L.C.A). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists.One sentence summaryThe host immune response in COVID-19.
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- 2021
21. Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.
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Masso-Silva, Jorge A, Moshensky, Alexander, Lam, Michael TY, Odish, Mazen, Patel, Arjun, Xu, Le, Hansen, Emily, Trescott, Samantha, Nguyen, Celina, Kim, Roy, Perofsky, Katherine, Perera, Samantha, Ma, Lauren, Pham, Josephine, Rolfsen, Mark, Olay, Jarod, Shin, John, Dan, Jennifer M, Abbott, Robert, Ramirez, Sydney, Alexander, Thomas H, Lin, Grace Y, Fuentes, Ana Lucia, Advani, Ira, Gunge, Deepti, Pretorius, Victor, Malhotra, Atul, Sun, Xin, Duran, Jason, Hepokoski, Mark, Crotty, Shane, Coufal, Nicole G, Meier, Angela, and Alexander, Laura E Crotty
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COVID-19 ,NETosis ,NETs ,Neutrophil ,Microbiology ,Biological Sciences ,Medical and Health Sciences - Abstract
BackgroundIncreased inflammation has been well defined in COVID-19, while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.MethodsBlood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.ResultsElevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified both at first measurement and across hospitalization (p
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- 2021
22. Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study
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Amoako, Angela, Andre, Dalles, van Bakel, Harm, Cognini, Christian C., Gleason, Charles, Gonzales-Reiche, Ana, van Kesteren, Morgan, Kleiner, Giulio, Lyttle, Neko, Mauldin, Jacob D., Monahan, Brian C., Nardulli, Jessica R., Oostenink, Annika, Paniz-Mondolfi, Alberto, Polanco, Jose, Ramírez, Juan David, Rooker, Aria, Sordillo, Emilia Mia, Srivastava, Komal, Cohn, Hallie, Bloom, Nathaniel, Cai, Gianna Y, Clark, Jordan J, Tarke, Alison, Bermúdez-González, Maria C, Altman, Deena R, Lugo, Luz Amarilis, Lobo, Francisco Pereira, Marquez, Susanna, Chen, Jin-Qiu, Ren, Wenlin, Qin, Lili, Yates, Jennifer L, Hunt, Danielle T, Lee, William T, Crotty, Shane, Krammer, Florian, Grifoni, Alba, Sette, Alessandro, Simon, Viviana, and Coelho, Camila H
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- 2023
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23. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection
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Dan, Jennifer M, Mateus, Jose, Kato, Yu, Hastie, Kathryn M, Yu, Esther Dawen, Faliti, Caterina E, Grifoni, Alba, Ramirez, Sydney I, Haupt, Sonya, Frazier, April, Nakao, Catherine, Rayaprolu, Vamseedhar, Rawlings, Stephen A, Peters, Bjoern, Krammer, Florian, Simon, Viviana, Saphire, Erica Ollmann, Smith, Davey M, Weiskopf, Daniela, Sette, Alessandro, and Crotty, Shane
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Biomedical and Clinical Sciences ,Immunology ,Immunization ,Lung ,Prevention ,Pneumonia ,Pneumonia & Influenza ,Emerging Infectious Diseases ,Vaccine Related ,Infectious Diseases ,Biodefense ,Infection ,Inflammatory and immune system ,Good Health and Well Being ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Neutralizing ,Antibodies ,Viral ,B-Lymphocytes ,CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,COVID-19 ,Cross-Sectional Studies ,Female ,Humans ,Immunologic Memory ,Longitudinal Studies ,Male ,Middle Aged ,Spike Glycoprotein ,Coronavirus ,United States ,Young Adult ,General Science & Technology - Abstract
Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
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- 2021
24. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases
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Tarke, Alison, Sidney, John, Kidd, Conner K, Dan, Jennifer M, Ramirez, Sydney I, Yu, Esther Dawen, Mateus, Jose, da Silva Antunes, Ricardo, Moore, Erin, Rubiro, Paul, Methot, Nils, Phillips, Elizabeth, Mallal, Simon, Frazier, April, Rawlings, Stephen A, Greenbaum, Jason A, Peters, Bjoern, Smith, Davey M, Crotty, Shane, Weiskopf, Daniela, Grifoni, Alba, and Sette, Alessandro
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Infectious Diseases ,Emerging Infectious Diseases ,Biodefense ,Pneumonia & Influenza ,Vaccine Related ,Immunization ,Prevention ,Lung ,Pneumonia ,2.1 Biological and endogenous factors ,Aetiology ,Infection ,Good Health and Well Being ,CD4+T cells ,CD8+ T cells ,COVID-19 ,HLA ,SARS-CoV-2 ,T cells ,epitopes - Abstract
T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens and precisely measure virus-specific CD4+ and CD8+ T cells, we study epitope-specific T cell responses of 99 convalescent coronavirus disease 2019 (COVID-19) cases. The SARS-CoV-2 proteome is probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of human leukocyte antigen (HLA) alleles for class II responses. For HLA class I, we study an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identify several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance are observed, which differ for CD4+ T cells, CD8+ T cells, and antibodies. The class I and class II epitopes are combined into epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4+ and CD8+ T cells.
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- 2021
25. Chronic E-Cigarette Aerosol Inhalation Alters the Immune State of the Lungs and Increases ACE2 Expression, Raising Concern for Altered Response and Susceptibility to SARS-CoV-2
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Masso-Silva, Jorge A, Moshensky, Alexander, Shin, John, Olay, Jarod, Nilaad, Sedtavut, Advani, Ira, Bojanowski, Christine M, Crotty, Shane, Li, Wei Tse, Ongkeko, Weg M, Singla, Sunit, and Alexander, Laura E Crotty
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Emerging Infectious Diseases ,Tobacco ,Tobacco Smoke and Health ,Prevention ,Biodefense ,Rare Diseases ,Electronic Nicotine Delivery Systems ,Lung ,Coronaviruses ,Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Respiratory ,Inflammatory and immune system ,Good Health and Well Being ,e-cigarette ,vaping ,ACE2 ,COVID-19 ,immunomodulation ,SARS-CoV-2 ,RNAseq ,lipidomics ,Physiology ,Medical Physiology ,Psychology ,Biochemistry and cell biology ,Medical physiology - Abstract
Conventional smoking is known to both increase susceptibility to infection and drive inflammation within the lungs. Recently, smokers have been found to be at higher risk of developing severe forms of coronavirus disease 2019 (COVID-19). E-cigarette aerosol inhalation (vaping) has been associated with several inflammatory lung disorders, including the recent e-cigarette or vaping product use-associated lung injury (EVALI) epidemic, and recent studies have suggested that vaping alters host susceptibility to pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the impact of vaping on lung inflammatory pathways, including the angiotensin-converting enzyme 2 (ACE2) receptor known to be involved in SARS-CoV-2 infection, mice were exposed to e-cigarette aerosols for 60 min daily for 1-6 months and underwent gene expression analysis. Hierarchical clustering revealed extensive gene expression changes occurred in the lungs of both inbred C57BL/6 mice and outbred CD1 mice, with 2,933 gene expression changes in C57BL/6 mice, and 2,818 gene expression changes in CD1 mice (>abs 1.25-fold change). Particularly, large reductions in IgA and CD4 were identified, indicating impairment of host responses to pathogens via reductions in immunoglobulins and CD4 T cells. CD177, facmr, tlr9, fcgr1, and ccr2 were also reduced, consistent with diminished host defenses via decreased neutrophils and/or monocytes in the lungs. Gene set enrichment (GSE) plots demonstrated upregulation of gene expression related to cell activation specifically in neutrophils. As neutrophils are a potential driver of acute lung injury in COVID-19, increased neutrophil activation in the lungs suggests that vapers are at higher risk of developing more severe forms of COVID-19. The receptor through which SARS-CoV-2 infects host cells, ACE2, was found to have moderate upregulation in mice exposed to unflavored vape pens, and further upregulation (six-fold) with JUUL mint aerosol exposure. No changes were found in mice exposed to unflavored Mod device-generated aerosols. These findings suggest that specific vaping devices and components of e-liquids have an effect on ACE2 expression, thus potentially increasing susceptibility to SARS-CoV-2. In addition, exposure to e-cigarette aerosols both with and without nicotine led to alterations in eicosanoid lipid profiles within the BAL. These data demonstrate that chronic, daily inhalation of e-cigarette aerosols fundamentally alters the inflammatory and immune state of the lungs. Thus, e-cigarette vapers may be at higher risk of developing infections and inflammatory disorders of the lungs.
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- 2021
26. Immunological memory to SARS-CoV-2 assessed for up to eight months after infection
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Dan, Jennifer M, Mateus, Jose, Kato, Yu, Hastie, Kathryn M, Yu, Esther Dawen, Faliti, Caterina E, Grifoni, Alba, Ramirez, Sydney I, Haupt, Sonya, Frazier, April, Nakao, Catherine, Rayaprolu, Vamseedhar, Rawlings, Stephen A, Peters, Bjoern, Krammer, Florian, Simon, Viviana, Saphire, Erica Ollmann, Smith, Davey M, Weiskopf, Daniela, Sette, Alessandro, and Crotty, Shane
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Biomedical and Clinical Sciences ,Immunology ,Vaccine Related ,Prevention ,Lung ,Immunization ,Biodefense ,Emerging Infectious Diseases ,Infectious Diseases ,Pneumonia ,Pneumonia & Influenza ,Inflammatory and immune system ,Infection ,Good Health and Well Being - Abstract
Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4 + T cells and CD8 + T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4 + T cell, and CD8 + T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
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- 2020
27. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases
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Tarke, Alison, Sidney, John, Kidd, Conner K, Dan, Jennifer M, Ramirez, Sydney I, Yu, Esther Dawen, Mateus, Jose, da Silva Antunes, Ricardo, Moore, Erin, Rubiro, Paul, Methot, Nils, Phillips, Elizabeth, Mallal, Simon, Frazier, April, Rawlings, Stephen A, Greenbaum, Jason A, Peters, Bjoern, Smith, Davey M, Crotty, Shane, Weiskopf, Daniela, Grifoni, Alba, and Sette, Alessandro
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,Genetics ,Vaccine Related ,Prevention ,Biodefense ,Emerging Infectious Diseases ,Lung ,Pneumonia ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being - Abstract
T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens, and precisely measure virus-specific CD4 + and CD8 + T cells, we studied epitope-specific T cell responses of approximately 100 convalescent COVID-19 cases. The SARS-CoV-2 proteome was probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of HLA alleles for class II responses. For HLA class I, we studied an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identified several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance were observed, which differed for CD4 + T cells, CD8 + T cells, and antibodies. The class I and class II epitopes were combined into new epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4 + and CD8 + T cells.
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- 2020
28. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity
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Moderbacher, Carolyn Rydyznski, Ramirez, Sydney I, Dan, Jennifer M, Grifoni, Alba, Hastie, Kathryn M, Weiskopf, Daniela, Belanger, Simon, Abbott, Robert K, Kim, Christina, Choi, Jinyong, Kato, Yu, Crotty, Eleanor G, Kim, Cheryl, Rawlings, Stephen A, Mateus, Jose, Tse, Long Ping Victor, Frazier, April, Baric, Ralph, Peters, Bjoern, Greenbaum, Jason, Saphire, Erica Ollmann, Smith, Davey M, Sette, Alessandro, and Crotty, Shane
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Biomedical and Clinical Sciences ,Immunology ,Emerging Infectious Diseases ,Lung ,Biodefense ,Infectious Diseases ,Vaccine Related ,Immunization ,Pneumonia ,Prevention ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Good Health and Well Being ,Acute Disease ,Adaptive Immunity ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Neutralizing ,Antibodies ,Viral ,Antigens ,Viral ,Betacoronavirus ,CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,COVID-19 ,Coronavirus Infections ,Cytokines ,Female ,Humans ,Male ,Middle Aged ,Pandemics ,Pneumonia ,Viral ,SARS-CoV-2 ,Severity of Illness Index ,Young Adult ,CD4 ,CD8 ,CXCL10 ,IP-10 ,Spike ,T cells ,adaptive immunity ,antibody ,coronavirus ,epitopes ,neutralizing antibodies ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.
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- 2020
29. Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity.
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Rydyznski Moderbacher, Carolyn, Ramirez, Sydney I, Dan, Jennifer M, Grifoni, Alba, Hastie, Kathryn M, Weiskopf, Daniela, Belanger, Simon, Abbott, Robert K, Kim, Christina, Choi, Jinyong, Kato, Yu, Crotty, Eleanor G, Kim, Cheryl, Rawlings, Stephen A, Mateus, Jose, Tse, Long Ping Victor, Frazier, April, Baric, Ralph, Peters, Bjoern, Greenbaum, Jason, Ollmann Saphire, Erica, Smith, Davey M, Sette, Alessandro, and Crotty, Shane
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CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,Humans ,Pneumonia ,Viral ,Coronavirus Infections ,Acute Disease ,Antibodies ,Viral ,Antigens ,Viral ,Cytokines ,Severity of Illness Index ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Young Adult ,Adaptive Immunity ,Antibodies ,Neutralizing ,Pandemics ,Betacoronavirus ,COVID-19 ,SARS-CoV-2 ,CD4 ,CD8 ,CXCL10 ,IP-10 ,Spike ,T cells ,adaptive immunity ,antibody ,coronavirus ,epitopes ,neutralizing antibodies ,Pneumonia ,Viral ,Antibodies ,Antigens ,and over ,Neutralizing ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.
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- 2020
30. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans
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Mateus, Jose, Grifoni, Alba, Tarke, Alison, Sidney, John, Ramirez, Sydney I, Dan, Jennifer M, Burger, Zoe C, Rawlings, Stephen A, Smith, Davey M, Phillips, Elizabeth, Mallal, Simon, Lammers, Marshall, Rubiro, Paul, Quiambao, Lorenzo, Sutherland, Aaron, Yu, Esther Dawen, da Silva Antunes, Ricardo, Greenbaum, Jason, Frazier, April, Markmann, Alena J, Premkumar, Lakshmanane, de Silva, Aravinda, Peters, Bjoern, Crotty, Shane, Sette, Alessandro, and Weiskopf, Daniela
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Biomedical and Clinical Sciences ,Immunology ,Pneumonia & Influenza ,Lung ,Infectious Diseases ,Pneumonia ,Vaccine Related ,Emerging Infectious Diseases ,Biotechnology ,Prevention ,Biodefense ,Good Health and Well Being ,Betacoronavirus ,Blood Donors ,CD4-Positive T-Lymphocytes ,COVID-19 ,Coronavirus Infections ,Cross Reactions ,Epitope Mapping ,Epitopes ,T-Lymphocyte ,Genome ,Viral ,Humans ,Immunologic Memory ,Open Reading Frames ,Pandemics ,Pneumonia ,Viral ,SARS-CoV-2 ,Sequence Homology ,General Science & Technology - Abstract
Many unknowns exist about human immune responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. SARS-CoV-2-reactive CD4+ T cells have been reported in unexposed individuals, suggesting preexisting cross-reactive T cell memory in 20 to 50% of people. However, the source of those T cells has been speculative. Using human blood samples derived before the SARS-CoV-2 virus was discovered in 2019, we mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2-specific CD4+ T cell repertoire. We demonstrate a range of preexisting memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses human coronavirus (HCoV)-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Thus, variegated T cell memory to coronaviruses that cause the common cold may underlie at least some of the extensive heterogeneity observed in coronavirus disease 2019 (COVID-19) disease.
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- 2020
31. The persistence of memory: defining, engineering, and measuring vaccine durability
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Palin, Amy C., Alter, Galit, Crotty, Shane, Ellebedy, Ali H., Lane, M. Chelsea, Lee, F. Eun-Hyung, Locci, Michela, Malaspina, Angela, Mallia, Conrad, McElrath, M. Juliana, Pulendran, Bali, Singh, Anjali, and D’Souza, M. Patricia
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- 2022
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32. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals
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Grifoni, Alba, Weiskopf, Daniela, Ramirez, Sydney I, Mateus, Jose, Dan, Jennifer M, Moderbacher, Carolyn Rydyznski, Rawlings, Stephen A, Sutherland, Aaron, Premkumar, Lakshmanane, Jadi, Ramesh S, Marrama, Daniel, de Silva, Aravinda M, Frazier, April, Carlin, Aaron F, Greenbaum, Jason A, Peters, Bjoern, Krammer, Florian, Smith, Davey M, Crotty, Shane, and Sette, Alessandro
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Biomedical and Clinical Sciences ,Immunology ,Pneumonia ,Immunization ,Lung ,Emerging Infectious Diseases ,Prevention ,Pneumonia & Influenza ,Biodefense ,Infectious Diseases ,Vaccine Related ,Infection ,Good Health and Well Being ,Betacoronavirus ,CD4-Positive T-Lymphocytes ,CD8-Positive T-Lymphocytes ,COVID-19 ,COVID-19 Vaccines ,Convalescence ,Coronavirus Infections ,Cross Reactions ,Epitopes ,T-Lymphocyte ,Humans ,Leukocytes ,Mononuclear ,Pandemics ,Pneumonia ,Viral ,SARS-CoV-2 ,Spike Glycoprotein ,Coronavirus ,Viral Proteins ,Viral Vaccines ,CD4 ,CD8 ,T cells ,coronavirus ,cross-reactivity ,epitopes ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in ∼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.
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- 2020
33. Long-primed germinal centres with enduring affinity maturation and clonal migration
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Lee, Jeong Hyun, Sutton, Henry J., Cottrell, Christopher A., Phung, Ivy, Ozorowski, Gabriel, Sewall, Leigh M., Nedellec, Rebecca, Nakao, Catherine, Silva, Murillo, Richey, Sara T., Torre, Jonathan L., Lee, Wen-Hsin, Georgeson, Erik, Kubitz, Michael, Hodges, Sam, Mullen, Tina-Marie, Adachi, Yumiko, Cirelli, Kimberly M., Kaur, Amitinder, Allers, Carolina, Fahlberg, Marissa, Grasperge, Brooke F., Dufour, Jason P., Schiro, Faith, Aye, Pyone P., Kalyuzhniy, Oleksandr, Liguori, Alessia, Carnathan, Diane G., Silvestri, Guido, Shen, Xiaoying, Montefiori, David C., Veazey, Ronald S., Ward, Andrew B., Hangartner, Lars, Burton, Dennis R., Irvine, Darrell J., Schief, William R., and Crotty, Shane
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- 2022
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34. Asymptomatic or symptomatic SARS-CoV-2 infection plus vaccination confers increased adaptive immunity to variants of concern
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Sun, Peifang, Ramos, Irene, Coelho, Camila H., Grifoni, Alba, Balinsky, Corey A., Vangeti, Sindhu, Tarke, Alison, Bloom, Nathaniel I., Jani, Vihasi, Jakubski, Silvia J., Boulifard, David A., Cooper, Elizabeth, Goforth, Carl W., Marayag, Jan, Marrone, Amethyst, Nunez, Edgar, White, Lindsey, Porter, Chad K., Sugiharto, Victor A., Schilling, Megan, Mahajan, Avinash S., Beckett, Charmagne, Sette, Alessandro, Sealfon, Stuart C., Crotty, Shane, and Letizia, Andrew G.
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- 2022
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35. Differential cell-intrinsic regulations of germinal center B and T cells by miR-146a and miR-146b.
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Cho, Sunglim, Lee, Hyang-Mi, Yu, I-Shing, Choi, Youn, Huang, Hsi-Yuan, Hashemifar, Somaye, Lin, Ling-Li, Chen, Mei-Chi, Afanasiev, Nikita, Khan, Aly, Lin, Shu-Wha, Rudensky, Alexander, Crotty, Shane, and Lu, Li-Fan
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Animals ,Autoantibodies ,Autoimmunity ,B-Lymphocytes ,Bone Marrow Cells ,CD40 Antigens ,Cell Differentiation ,Gene Expression Regulation ,Germinal Center ,Immunity ,Humoral ,Interleukin-4 ,Mice ,Mice ,Transgenic ,MicroRNAs ,Primary Cell Culture ,Protein Isoforms ,Signal Transduction ,T-Lymphocytes ,Helper-Inducer - Abstract
Reciprocal interactions between B and follicular T helper (Tfh) cells orchestrate the germinal center (GC) reaction, a hallmark of humoral immunity. Abnormal GC responses could lead to the production of pathogenic autoantibodies and the development of autoimmunity. Here we show that miR-146a controls GC responses by targeting multiple CD40 signaling pathway components in B cells; by contrast, loss of miR-146a in T cells does not alter humoral responses. However, specific deletion of both miR-146a and its paralog, miR-146b, in T cells increases Tfh cell numbers and enhanced GC reactions. Thus, our data reveal differential cell-intrinsic regulations of GC B and Tfh cells by miR-146a and miR-146b. Together, members of the miR-146 family serve as crucial molecular brakes to coordinately control GC reactions to generate protective humoral responses without eliciting unwanted autoimmunity.
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- 2018
36. Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions
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Choi, Jinyong, primary, Crotty, Shane, additional, and Choi, Youn Soo, additional
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- 2024
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37. B cells expressing authentic naive human VRC01-class BCRs can be recruited to germinal centers and affinity mature in multiple independent mouse models
- Author
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Huang, Deli, Abbott, Robert K., Havenar-Daughton, Colin, Skog, Patrick D., Al-Kolla, Rita, Groschel, Bettina, Blane, Tanya R., Menis, Sergey, Tran, Jenny Tuyet, Thinnes, Theresa C., Volpi, Sabrina A., Liguori, Alessia, Schiffner, Torben, Villegas, Sophia M., Kalyuzhniy, Oleksandr, Pintea, Mark, Voss, James E., Phelps, Nicole, Tingle, Ryan, Rodriguez, Alberto R., Martin, Greg, Kupryianov, Sergey, deCamp, Allan, Schief, William R., Nemazee, David, and Crotty, Shane
- Published
- 2020
38. Bcl6-Mediated Transcriptional Regulation of Follicular Helper T cells (TFH)
- Author
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Choi, Jinyong and Crotty, Shane
- Published
- 2021
- Full Text
- View/download PDF
39. Author Correction: Long-primed germinal centres with enduring affinity maturation and clonal migration
- Author
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Lee, Jeong Hyun, Sutton, Henry J., Cottrell, Christopher A., Phung, Ivy, Ozorowski, Gabriel, Sewall, Leigh M., Nedellec, Rebecca, Nakao, Catherine, Silva, Murillo, Richey, Sara T., Torres, Jonathan L., Lee, Wen-Hsin, Georgeson, Erik, Kubitz, Michael, Hodges, Sam, Mullen, Tina-Marie, Adachi, Yumiko, Cirelli, Kimberly M., Kaur, Amitinder, Allers, Carolina, Fahlberg, Marissa, Grasperge, Brooke F., Dufour, Jason P., Schiro, Faith, Aye, Pyone P., Kalyuzhniy, Oleksandr, Liguori, Alessia, Carnathan, Diane G., Silvestri, Guido, Shen, Xiaoying, Montefiori, David C., Veazey, Ronald S., Ward, Andrew B., Hangartner, Lars, Burton, Dennis R., Irvine, Darrell J., Schief, William R., and Crotty, Shane
- Published
- 2023
- Full Text
- View/download PDF
40. Author Correction: The persistence of memory: defining, engineering, and measuring vaccine durability
- Author
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Palin, Amy C., Alter, Galit, Crotty, Shane, Ellebedy, Ali H., Lane, M. Chelsea, Lee, F. Eun-Hyung, Locci, Michela, Malaspina, Angela, Mallia, Conrad, McElrath, M. Juliana, Pulendran, Bali, Singh, Anjali, and D’Souza, M. Patricia
- Published
- 2023
- Full Text
- View/download PDF
41. NVX-CoV2373 vaccination induces functional SARS-CoV-2-specific [CD4.sup.+] and [CD8.sup.+] T cell responses
- Author
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Moderbacher, Carolyn Rydyznski, Kim, Christina, Mateus, Jose, Plested, Joyce, Zhu, Mingzhu, Cloney-Clark, Shane, Weiskopf, Daniela, Sette, Alessandro, Fries, Louis, Glenn, Gregory, and Crotty, Shane
- Subjects
Novavax Inc. -- Product development ,Biotechnology industry -- Product development ,Tumor necrosis factor -- Analysis ,Health care industry ,Covovax (Vaccine) -- Dosage and administration - Abstract
NVX-CoV2373 is an adjuvanted recombinant full-length SARS-CoV-2 spike trimer protein vaccine demonstrated to be protective against COVID-19 in efficacy trials. Here we demonstrate that vaccinated individuals made [CD4.sup.+] T cell responses after 1 and 2 doses of NVX-CoV2373, and a subset of individuals made [CD8.sup.+] T cell responses. Characterization of the vaccine-elicited [CD8.sup.+] T cells demonstrated IFN-[gamma] production. Characterization of the vaccine-elicited [CD4.sup.+] T cells revealed both circulating T follicular helper (cTfh) cells and Th1 cells ([IFN-[gamma].sup.+], [TNF-[alpha].sup.+], and [IL-2.sup.+]) were detectable within 7 days of the primary immunization. Spike-specific [CD4.sup.+] T cells were correlated with the magnitude of the later SARS-CoV-2-neutralizing antibody titers, indicating that robust generation of [CD4.sup.+] T cells, capable of supporting humoral immune responses, may be a key characteristic of NVX-CoV2373 that utilizes Matrix-M adjuvant., Introduction The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused immense morbidity and mortality. This global crisis has been met with an unprecedented surge [...]
- Published
- 2022
- Full Text
- View/download PDF
42. Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort.
- Author
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Landais, Elise, Huang, Xiayu, Havenar-Daughton, Colin, Murrell, Ben, Price, Matt A, Wickramasinghe, Lalinda, Ramos, Alejandra, Bian, Charoan B, Simek, Melissa, Allen, Susan, Karita, Etienne, Kilembe, William, Lakhi, Shabir, Inambao, Mubiana, Kamali, Anatoli, Sanders, Eduard J, Anzala, Omu, Edward, Vinodh, Bekker, Linda-Gail, Tang, Jianming, Gilmour, Jill, Kosakovsky-Pond, Sergei L, Phung, Pham, Wrin, Terri, Crotty, Shane, Godzik, Adam, and Poignard, Pascal
- Subjects
Humans ,HIV Infections ,AIDS Vaccines ,HIV Antibodies ,Epitopes ,B-Lymphocyte ,Enzyme-Linked Immunosorbent Assay ,Cohort Studies ,Longitudinal Studies ,Adult ,Middle Aged ,Africa South of the Sahara ,Female ,Male ,env Gene Products ,Human Immunodeficiency Virus ,Young Adult ,Antibodies ,Neutralizing ,Antibodies ,Neutralizing ,Epitopes ,B-Lymphocyte ,env Gene Products ,Human Immunodeficiency Virus ,Virology ,Microbiology ,Immunology ,Medical Microbiology - Abstract
Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.
- Published
- 2016
43. 2291. SARS-CoV-2 Viral Kinetics Among Immunologically Naïve Adults: Comparison by Variant and Reinfection Status
- Author
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Doll, Margaret K, primary, Shakoor, Brianna Levenson, additional, Kimball, Louise E, additional, Crukley, Jeffery, additional, Ozbek, Nina, additional, Blazevic, Rachel L, additional, Mose, Larry, additional, Boonyaratanakornkit, Jim, additional, Stevens-Ayers, Terry L, additional, Cornell, Kevin, additional, Sheppard, Benjamin D, additional, Hampson, Emma, additional, Sharmin, Faria, additional, Goodwin, Benjamin, additional, Dan, Jennifer M, additional, Archie, Tom, additional, O’Connor, Terry, additional, Boeckh, Michael J, additional, Crotty, Shane, additional, and Waghmare, Alpana, additional
- Published
- 2023
- Full Text
- View/download PDF
44. Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study
- Author
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Cohn, Hallie, primary, Bloom, Nathaniel, additional, Cai, Gianna Y, additional, Clark, Jordan J, additional, Tarke, Alison, additional, Bermúdez-González, Maria C, additional, Altman, Deena R, additional, Lugo, Luz Amarilis, additional, Lobo, Francisco Pereira, additional, Marquez, Susanna, additional, Chen, Jin-Qiu, additional, Ren, Wenlin, additional, Qin, Lili, additional, Yates, Jennifer L, additional, Hunt, Danielle T, additional, Lee, William T, additional, Crotty, Shane, additional, Krammer, Florian, additional, Grifoni, Alba, additional, Sette, Alessandro, additional, Simon, Viviana, additional, Coelho, Camila H, additional, Amoako, Angela, additional, Andre, Dalles, additional, van Bakel, Harm, additional, Cognini, Christian C., additional, Gleason, Charles, additional, Gonzales-Reiche, Ana, additional, van Kesteren, Morgan, additional, Kleiner, Giulio, additional, Lyttle, Neko, additional, Mauldin, Jacob D., additional, Monahan, Brian C., additional, Nardulli, Jessica R., additional, Oostenink, Annika, additional, Paniz-Mondolfi, Alberto, additional, Polanco, Jose, additional, Ramírez, Juan David, additional, Rooker, Aria, additional, Sordillo, Emilia Mia, additional, and Srivastava, Komal, additional
- Published
- 2023
- Full Text
- View/download PDF
45. Cross-reactive memory T cells and herd immunity to SARS-CoV-2
- Author
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Lipsitch, Marc, Grad, Yonatan H., Sette, Alessandro, and Crotty, Shane
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- 2020
- Full Text
- View/download PDF
46. Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM
- Author
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Antanasijevic, Aleksandar, Sewall, Leigh M., Cottrell, Christopher A., Carnathan, Diane G., Jimenez, Luis E., Ngo, Julia T., Silverman, Jennifer B., Groschel, Bettina, Georgeson, Erik, Bhiman, Jinal, Bastidas, Raiza, LaBranche, Celia, Allen, Joel D., Copps, Jeffrey, Perrett, Hailee R., Rantalainen, Kimmo, Cannac, Fabien, Yang, Yuhe R., de la Peña, Alba Torrents, Rocha, Rebeca Froes, Berndsen, Zachary T., Baker, David, King, Neil P., Sanders, Rogier W., Moore, John P., Crotty, Shane, Crispin, Max, Montefiori, David C., Burton, Dennis R., Schief, William R., Silvestri, Guido, and Ward, Andrew B.
- Published
- 2021
- Full Text
- View/download PDF
47. Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naïve human B cells
- Author
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Lee, Jeong Hyun, Toy, Laura, Kos, Justin T., Safonova, Yana, Schief, William R., Havenar-Daughton, Colin, Watson, Corey T., and Crotty, Shane
- Published
- 2021
- Full Text
- View/download PDF
48. Bcl-6 is the nexus transcription factor of T follicular helper cells via repressor-of-repressor circuits
- Author
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Choi, Jinyong, Diao, Huitian, Faliti, Caterina E., Truong, Jacquelyn, Rossi, Meghan, Bélanger, Simon, Yu, Bingfei, Goldrath, Ananda W., Pipkin, Matthew E., and Crotty, Shane
- Published
- 2020
- Full Text
- View/download PDF
49. Engineered immunogen binding to alum adjuvant enhances humoral immunity
- Author
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Moyer, Tyson J., Kato, Yu, Abraham, Wuhbet, Chang, Jason Y. H., Kulp, Daniel W., Watson, Nicki, Turner, Hannah L., Menis, Sergey, Abbott, Robert K., Bhiman, Jinal N., Melo, Mariane B., Simon, Hayley A., Herrera-De la Mata, Sara, Liang, Shu, Seumois, Gregory, Agarwal, Yash, Li, Na, Burton, Dennis R., Ward, Andrew B., Schief, William R., Crotty, Shane, and Irvine, Darrell J.
- Published
- 2020
- Full Text
- View/download PDF
50. The Transcription Factor NFAT Promotes Exhaustion of Activated CD8+ T Cells
- Author
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Martinez, Gustavo J, Pereira, Renata M, Äijö, Tarmo, Kim, Edward Y, Marangoni, Francesco, Pipkin, Matthew E, Togher, Susan, Heissmeyer, Vigo, Zhang, Yi Chen, Crotty, Shane, Lamperti, Edward D, Ansel, K Mark, Mempel, Thorsten R, Lähdesmäki, Harri, Hogan, Patrick G, and Rao, Anjana
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Cancer ,Biotechnology ,Genetics ,2.1 Biological and endogenous factors ,5.2 Cellular and gene therapies ,Aetiology ,Development of treatments and therapeutic interventions ,Animals ,CD8-Positive T-Lymphocytes ,Cells ,Cultured ,Clonal Anergy ,Gene Expression Regulation ,Listeria monocytogenes ,Listeriosis ,Lymphocyte Activation ,Mice ,Mice ,Transgenic ,NFATC Transcription Factors ,Neoplasms ,Promoter Regions ,Genetic ,Receptors ,Antigen ,T-Cell ,Recombinant Proteins ,Transcription Factor AP-1 - Abstract
During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.
- Published
- 2015
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