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1. Transcription factor EGR2 controls homing and pathogenicity of TH17 cells in the central nervous system

Author

Gao, Yuanyuan, Wang, Yan, Chauss, Daniel, Villarino, Alejandro V., Link, Verena M., Nagashima, Hiroyuki, Spinner, Camille A., Koparde, Vishal N., Bouladoux, Nicolas, Abers, Michael S., Break, Timothy J., Chopp, Laura B., Park, Jung-Hyun, Zhu, Jinfang, Wiest, David L., Leonard, Warren J., Lionakis, Michail S., O’Shea, John J., Afzali, Behdad, Belkaid, Yasmine, and Lazarevic, Vanja

Published
2023
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2. Response to Comments on “Aberrant type 1 immunity drives susceptibility to mucosal fungal infections”

Author

Break, Timothy J, Oikonomou, Vasileios, Dutzan, Nicolas, Desai, Jigar V, Swidergall, Marc, Freiwald, Tilo, Chauss, Daniel, Harrison, Oliver J, Alejo, Julie, Williams, Drake W, Pittaluga, Stefania, Lee, Chyi-Chia R, Bouladoux, Nicolas, Swamydas, Muthulekha, Hoffman, Kevin W, Greenwell-Wild, Teresa, Bruno, Vincent M, Rosen, Lindsey B, Lwin, Wint, Renteria, Andy, Pontejo, Sergio M, Shannon, John P, Myles, Ian A, Olbrich, Peter, Ferré, Elise MN, Schmitt, Monica, Martin, Daniel, Core16, Genomics and Computational Biology, Barber, Daniel L, Solis, Norma V, Notarangelo, Luigi D, Serreze, David V, Matsumoto, Mitsuru, Hickman, Heather D, Murphy, Philip M, Anderson, Mark S, Lim, Jean K, Holland, Steven M, Filler, Scott G, Afzali, Behdad, Belkaid, Yasmine, Moutsopoulos, Niki M, and Lionakis, Michail S

Subjects
Autoimmune Disease, Clinical Research, Infectious Diseases, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Humans, Immunity, Mucosal, Mucous Membrane, Mycoses, Genomics and Computational Biology Core16, General Science & Technology
Abstract

Puel and Casanova and Kisand et al. challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire-deficient mice, with strong corroborative evidence in patients.

Published
2021

3. Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

Author

Break, Timothy J, Oikonomou, Vasileios, Dutzan, Nicolas, Desai, Jigar V, Swidergall, Marc, Freiwald, Tilo, Chauss, Daniel, Harrison, Oliver J, Alejo, Julie, Williams, Drake W, Pittaluga, Stefania, Lee, Chyi-Chia R, Bouladoux, Nicolas, Swamydas, Muthulekha, Hoffman, Kevin W, Greenwell-Wild, Teresa, Bruno, Vincent M, Rosen, Lindsey B, Lwin, Wint, Renteria, Andy, Pontejo, Sergio M, Shannon, John P, Myles, Ian A, Olbrich, Peter, Ferré, Elise MN, Schmitt, Monica, Martin, Daniel, Core16, Genomics and Computational Biology, Barber, Daniel L, Solis, Norma V, Notarangelo, Luigi D, Serreze, David V, Matsumoto, Mitsuru, Hickman, Heather D, Murphy, Philip M, Anderson, Mark S, Lim, Jean K, Holland, Steven M, Filler, Scott G, Afzali, Behdad, Belkaid, Yasmine, Moutsopoulos, Niki M, and Lionakis, Michail S

Subjects
Autoimmune Disease, Emerging Infectious Diseases, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Inflammatory and immune system, Adolescent, Adult, Aged, Animals, Candida albicans, Candidiasis, Chronic Mucocutaneous, Disease Models, Animal, Female, Humans, Immunity, Mucosal, Immunologic Surveillance, Interferon-gamma, Interleukins, Janus Kinases, Male, Mice, Mice, Inbred BALB C, Middle Aged, Mouth Mucosa, Polyendocrinopathies, Autoimmune, Receptors, Interleukin-17, STAT1 Transcription Factor, T-Lymphocytes, Young Adult, Genomics and Computational Biology Core, General Science & Technology
Abstract

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.

Published
2021

5. The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1

Author

Oikonomou, Vasileios, primary, Smith, Grace, additional, Constantine, Gregory M., additional, Schmitt, Monica M., additional, Ferré, Elise M.N., additional, Alejo, Julie C., additional, Riley, Deanna, additional, Kumar, Dhaneshwar, additional, Dos Santos Dias, Lucas, additional, Pechacek, Joseph, additional, Hadjiyannis, Yannis, additional, Webb, Taura, additional, Seifert, Bryce A., additional, Ghosh, Rajarshi, additional, Walkiewicz, Magdalena, additional, Martin, Daniel, additional, Besnard, Marine, additional, Snarr, Brendan D., additional, Deljookorani, Shiva, additional, Lee, Chyi-chia R., additional, DiMaggio, Tom, additional, Barber, Princess, additional, Rosen, Lindsey B., additional, Cheng, Aristine, additional, Rastegar, Andre, additional, de Jesus, Adriana A., additional, Stoddard, Jennifer, additional, Kuehn, Hye Sun, additional, Break, Timothy J., additional, Kong, Heidi H., additional, Castelo-Soccio, Leslie, additional, Colton, Ben, additional, Warner, Blake M., additional, Kleiner, David E., additional, Quezado, Martha M., additional, Davis, Jeremy L., additional, Fennelly, Kevin P., additional, Olivier, Kenneth N., additional, Rosenzweig, Sergio D., additional, Suffredini, Anthony F., additional, Anderson, Mark S., additional, Swidergall, Marc, additional, Guillonneau, Carole, additional, Notarangelo, Luigi D., additional, Goldbach-Mansky, Raphaela, additional, Neth, Olaf, additional, Monserrat-Garcia, Maria Teresa, additional, Valverde-Fernandez, Justo, additional, Lucena, Jose Manuel, additional, Gomez-Gila, Ana Lucia, additional, Garcia Rojas, Angela, additional, Seppänen, Mikko R. J., additional, Lohi, Jouko, additional, Hero, Matti, additional, Laakso, Saila, additional, Klemetti, Paula, additional, Lundberg, Vanja, additional, Ekwall, Olov, additional, Olbrich, Peter, additional, Winer, Karen K., additional, Afzali, Behdad, additional, Moutsopoulos, Niki M., additional, Holland, Steven M., additional, Heller, Theo, additional, Pittaluga, Stefania, additional, and Lionakis, Michail S., additional

Published
2024
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6. CX3CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

Author

Break, Timothy J, Jaeger, Martin, Solis, Norma V, Filler, Scott G, Rodriguez, Carlos A, Lim, Jean K, Lee, Chyi-Chia Richard, Sobel, Jack D, Netea, Mihai G, and Lionakis, Michail S

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Infectious Diseases, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Alleles, Animals, CX3C Chemokine Receptor 1, Candida albicans, Candidiasis, Candidiasis, Vulvovaginal, Disease Models, Animal, Female, Gastrointestinal Tract, Gene Expression, Host-Pathogen Interactions, Humans, Interleukin-17, Interleukin-23, Interleukins, Mice, Mice, Inbred C57BL, Mice, Knockout, Opportunistic Infections, Receptors, Chemokine, Tongue, Vagina, Agricultural and Veterinary Sciences, Medical and Health Sciences, Immunology, Medical microbiology
Abstract

Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 allele CX3CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections.

Published
2015

7. On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier

Author

Dutzan, Nicolas, Abusleme, Loreto, Bridgeman, Hayley, Greenwell-Wild, Teresa, Zangerle-Murray, Tamsin, Fife, Mark E., Bouladoux, Nicolas, Linley, Holly, Brenchley, Laurie, Wemyss, Kelly, Calderon, Gloria, Hong, Bo-Young, Break, Timothy J., Bowdish, Dawn M.E., Lionakis, Michail S., Jones, Simon A., Trinchieri, Giorgio, Diaz, Patricia I., Belkaid, Yasmine, Konkel, Joanne E., and Moutsopoulos, Niki M.

Published
2017
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11. Oral epithelial IL-22/STAT3 signaling licenses IL-17–mediated immunity to oral mucosal candidiasis

Author

Aggor, Felix E. Y., primary, Break, Timothy J., additional, Trevejo-Nuñez, Giraldina, additional, Whibley, Natasha, additional, Coleman, Bianca M., additional, Bailey, Rachel D., additional, Kaplan, Daniel H., additional, Naglik, Julian R., additional, Shan, Wei, additional, Shetty, Amol C., additional, McCracken, Carrie, additional, Durum, Scott K., additional, Biswas, Partha S., additional, Bruno, Vincent M., additional, Kolls, Jay K., additional, Lionakis, Michail S., additional, and Gaffen, Sarah L., additional

Published
2020
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12. Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance

Author

Ferré, Elise M. N., primary, Break, Timothy J., additional, Burbelo, Peter D., additional, Allgäuer, Michael, additional, Kleiner, David E., additional, Jin, Dakai, additional, Xu, Ziyue, additional, Folio, Les R., additional, Mollura, Daniel J., additional, Swamydas, Muthulekha, additional, Gu, Wenjuan, additional, Hunsberger, Sally, additional, Lee, Chyi-Chia R., additional, Bondici, Anamaria, additional, Hoffman, Kevin W., additional, Lim, Jean K., additional, Dobbs, Kerry, additional, Niemela, Julie E., additional, Fleisher, Thomas A., additional, Hsu, Amy P., additional, Snow, Laquita N., additional, Darnell, Dirk N., additional, Ojaimi, Samar, additional, Cooper, Megan A., additional, Bozzola, Martin, additional, Kleiner, Gary I., additional, Martinez, Juan C., additional, Deterding, Robin R., additional, Kuhns, Douglas B., additional, Heller, Theo, additional, Winer, Karen K., additional, Rajan, Arun, additional, Holland, Steven M., additional, Notarangelo, Luigi D., additional, Fennelly, Kevin P., additional, Olivier, Kenneth N., additional, and Lionakis, Michail S., additional

Published
2019
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14. VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice

Author

Break, Timothy J, primary, Desai, Jigar V, additional, Healey, Kelley R, additional, Natarajan, Mukil, additional, Ferre, Elise M N, additional, Henderson, Christina, additional, Zelazny, Adrian, additional, Siebenlist, Ulrich, additional, Yates, Christopher M, additional, Cohen, Oren J, additional, Schotzinger, Robert J, additional, Perlin, David S, additional, Garvey, Edward P, additional, and Lionakis, Michail S, additional

Published
2018
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16. VT-1161 protects mice against oropharyngeal candidiasis caused by fluconazole-susceptible and -resistant Candida albicans

Author

Break, Timothy J, primary, Desai, Jigar V, additional, Natarajan, Mukil, additional, Ferre, Elise M N, additional, Henderson, Christina, additional, Zelazny, Adrian M, additional, Siebenlist, Ulrich, additional, Hoekstra, William J, additional, Schotzinger, Robert J, additional, Garvey, Edward P, additional, and Lionakis, Michail S, additional

Published
2017
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17. PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients

Author

Zhang, Yuan, primary, Ma, Chi A., additional, Lawrence, Monica G., additional, Break, Timothy J., additional, O’Connell, Michael P., additional, Lyons, Jonathan J., additional, López, Diego B., additional, Barber, John S., additional, Zhao, Yongge, additional, Barber, Daniel L., additional, Freeman, Alexandra F., additional, Holland, Steven M., additional, Lionakis, Michail S., additional, and Milner, Joshua D., additional

Published
2017
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19. VT-1598 Inhibits the in vitro Growth of Mucosal Candida Isolates and Protects Against Oropharyngeal Candidiasis in IL-17 Deficient Mice

Author

Break, Timothy J, primary, Desai, Jigar V, additional, Natarajan, Mukil, additional, Ferre, Elise, additional, Henderson, Christina, additional, Zelazny, Adrian M, additional, Yates, Christopher M, additional, Cohen, Oren J, additional, Schotzinger, Robert J, additional, Garvey, Edward P, additional, and Lionakis, Michail, additional

Published
2017
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21. Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Author

Ferre, Elise M.N., primary, Rose, Stacey R., additional, Rosenzweig, Sergio D., additional, Burbelo, Peter D., additional, Romito, Kimberly R., additional, Niemela, Julie E., additional, Rosen, Lindsey B., additional, Break, Timothy J., additional, Gu, Wenjuan, additional, Hunsberger, Sally, additional, Browne, Sarah K., additional, Hsu, Amy P., additional, Rampertaap, Shakuntala, additional, Swamydas, Muthulekha, additional, Collar, Amanda L., additional, Kong, Heidi H., additional, Lee, Chyi-Chia Richard, additional, Chascsa, David, additional, Simcox, Thomas, additional, Pham, Angela, additional, Bondici, Anamaria, additional, Natarajan, Mukil, additional, Monsale, Joseph, additional, Kleiner, David E., additional, Quezado, Martha, additional, Alevizos, Ilias, additional, Moutsopoulos, Niki M., additional, Yockey, Lynne, additional, Frein, Cathleen, additional, Soldatos, Ariane, additional, Calvo, Katherine R., additional, Adjemian, Jennifer, additional, Similuk, Morgan N., additional, Lang, David M., additional, Stone, Kelly D., additional, Uzel, Gulbu, additional, Kopp, Jeffrey B., additional, Bishop, Rachel J., additional, Holland, Steven M., additional, Olivier, Kenneth N., additional, Fleisher, Thomas A., additional, Heller, Theo, additional, Winer, Karen K., additional, and Lionakis, Michail S., additional

Published
2016
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22. CD8+ T cells produce a dialyzable antigen-specific activator of dendritic cells

Author

Myles, Ian A, primary, Zhao, Ming, additional, Nardone, Glenn, additional, Olano, Lisa R, additional, Reckhow, Jensen D, additional, Saleem, Danial, additional, Break, Timothy J, additional, Lionakis, Michail S, additional, Myers, Timothy G, additional, Gardina, Paul J, additional, Kirkpatrick, Charles H, additional, Holland, Steven M, additional, and Datta, Sandip K, additional

Published
2016
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24. CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival

Author

Swamydas, Muthulekha, primary, Gao, Ji-Liang, additional, Break, Timothy J., additional, Johnson, Melissa D., additional, Jaeger, Martin, additional, Rodriguez, Carlos A., additional, Lim, Jean K., additional, Green, Nathaniel M., additional, Collar, Amanda L., additional, Fischer, Brett G., additional, Lee, Chyi-Chia Richard, additional, Perfect, John R., additional, Alexander, Barbara D., additional, Kullberg, Bart-Jan, additional, Netea, Mihai G., additional, Murphy, Philip M., additional, and Lionakis, Michail S., additional

Published
2016
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27. VT-1161 protects mice against oropharyngeal candidiasis caused by fluconazole-susceptible and -resistant Candida albicans.

Author

Break, Timothy J., Desai, Jigar V., Natarajan, Mukil, Ferre, Elise M. N., Henderson, Christina, Zelazny, Adrian M., Siebenlist, Ulrich, Hoekstra, William J., Schotzinger, Robert J., Garvey, Edward P., and Lionakis, Michail S.

Subjects
*CANDIDIASIS treatment, *OROPHARYNX, *FLUCONAZOLE, *CANDIDA albicans, *DRUG resistance, *MICROBIAL sensitivity tests, *DISEASES, *THERAPEUTICS, *FUNGI
Abstract

Background: Candida albicans, the most common human fungal pathogen, causes chronic mucosal infections in patients with inborn errors of IL-17 immunity that rely heavily on chronic, often lifelong, azole antifungal agents for treatment. However, a rise in azole resistance has predicated a need for developing new antifungal drugs.Objectives: To test the in vitro and in vivo efficacy of VT-1161 and VT-1129 in the treatment of oropharyngeal candidiasis with azole-susceptible or -resistant C. albicans strains.Methods: MICs of VT-1161, VT-1129 and nine licensed antifungal drugs were determined for 31 Candida clinical isolates. The drug concentrations in mouse serum and tongues were measured following oral administration. IL-17-signalling-deficient Act1-/- mice were infected with fluconazole-susceptible or fluconazole-resistant C. albicans strains, and the amount of mucosal fungal burden was determined after fluconazole or VT-1161 treatment.Results: Fourteen isolates (45%) were not fluconazole susceptible (MIC ≥4 mg/L). VT-1161 and VT-1129 showed significant in vitro activity against the majority of the 31 mucosal clinical isolates (MIC50 0.03 and 0.06 mg/L, respectively), including Candida glabrata (MIC50, 0.125 and 0.25 mg/L, respectively). After oral doses, VT-1161 and VT-1129 concentrations in mouse serum and tongues were well above their MIC50 values. VT-1161 was highly effective as treatment of both fluconazole-susceptible and -resistant oropharyngeal candidiasis in Act1-/- mice.Conclusions: VT-1129 and VT-1161 exhibit significant in vitro activity against Candida strains, including fluconazole-resistant C. albicans and C. glabrata. VT-1161 administration in mice results in significant mucosal drug accumulation and eradicates infection caused by fluconazole-susceptible and -resistant Candida strains. [ABSTRACT FROM AUTHOR]

Published
2018
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29. Batf3-dependent CD103+ dendritic cell accumulation is dispensable for mucosal and systemic antifungal host defense.

Author

Break, Timothy J., Hoffman, Kevin W., Swamydas, Muthulekha, Lee, Chyi-Chia Richard, Lim, Jean K., and Lionakis, Michail S.

Subjects
*DENDRITIC cells, *CD antigens, *ANTIFUNGAL agents, *IMMUNE response, *TRANSCRIPTION factors
Abstract

Dendritic cells (DCs) are critical for defense against a variety of pathogens and the formation of adaptive immune responses. The transcription factor Batf3 is critical for the development of CD103+CD11b- DCs, which promote IL-12-dependent protective immunity during viral and parasitic infections, dampen Th2 immunity during helminthic infection, and exert detrimental effects during bacterial infection. Whether CD103+ DCs modulate immunity during systemic or mucosal fungal disease remains unknown. Herein, we report that Batf3 is critical for accumulation of CD103+ DCs in the kidney and tongue at steady state, for their expansion during systemic and oropharyngeal candidiasis, and for tissue-specific production of IL-12 in kidney but not tongue during systemic and oropharyngeal candidiasis, respectively. Importantly, deficiency of CD103+ DCs does not impair survival or fungal clearance during systemic or oropharyngeal candidiasis, indicating that Batf3-dependent CD103+ DC accumulation mediates pathogen- and tissue-specific immune effects. [ABSTRACT FROM AUTHOR]

Published
2016
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34. CD8+T cells produce a dialyzable antigen-specific activator of dendritic cells

Author

Myles, Ian A., Zhao, Ming, Nardone, Glenn, Olano, Lisa R., Reckhow, Jensen D., Saleem, Danial, Break, Timothy J., Lionakis, Michail S., Myers, Timothy G., Gardina, Paul J., Kirkpatrick, Charles H., Holland, Steven M., and Datta, Sandip K.

Abstract

Cellular lysates from PPD+donors have been reported to transfer tuberculin reactivity to naïve recipients, but not diphtheria reactivity, and vice versa. A historically controversial topic, the terms “transfer factor” and “DLE” were used to characterize the reactivity-transferring properties of lysates. Intrigued by these reported phenomena, we found that the cellular extract derived from antigen-specific memory CD8+T cells induces IL-6 from antigen-matched APCs. This ultimately elicits IL-17 from bystander memory CD8+T cells. We have identified that dialyzable peptide sequences, S100a9, and the TCR ß chain from CD8+T cells contribute to the molecular nature of this activity. We further show that extracts from antigen-targeted T cells enhance immunity to Staphylococcus aureusand Candida albicans. These effects are sensitive to immunization protocols and extraction methodology in ways that may explain past discrepancies in the reproducibility of passive cellular immunity. Lysates from CD8+T cells transfer passive IL-17-mediated cellular immunity through elements of the TCR and S100; an opportunity to elucidate the structure, role, and therapeutic potential.

Published
2017
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35. PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients

Author

Zhang, Yuan, Ma, Chi A., Lawrence, Monica G., Break, Timothy J., O’Connell, Michael P., Lyons, Jonathan J., Barber, John S., Zhao, Yongge, Barber, Daniel L., Freeman, Alexandra F., Holland, Steven M., Lionakis, Michail S., Milner, Joshua D., and Lopez, Diego

Subjects
Brief Definitive Report
Abstract

Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation—known to inhibit Th17 differentiation in mouse models—was markedly enhanced as well. Overexpression of SOCS3 strongly inhibited phosphorylation of STAT1 and PD-L1 up-regulation, suggesting that diminished SOCS3 expression may lead to the observed effects. Defects in Th17 differentiation could be partially overcome in vitro via PD-L1 inhibition and in a mouse model of STAT3 loss-of-function by crossing them with PD-1 knockout mice. PD-L1 may be a potential therapeutic target in several genetic diseases of immune deficiency affecting cytokine signaling., Version of Record

Published
2017
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36. CX3CR1 Is Dispensable for Control of Mucosal Candida albicansInfections in Mice and Humans

Author

Break, Timothy J., Jaeger, Martin, Solis, Norma V., Filler, Scott G., Rodriguez, Carlos A., Lim, Jean K., Lee, Chyi-Chia Richard, Sobel, Jack D., Netea, Mihai G., and Lionakis, Michail S.

Abstract

ABSTRACTCandida albicansis part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candidainfections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosal C. albicansinfection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 allele CX3CR1-M280was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candidainfections.

Published
2015
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37. TECHNICAL COMMENT ABSTRACTS.

Author

Puel, Anne, Casanova, Jean-Laurent, Kisand, Kai, Meager, Anthony, Hayday, Adrian, Willcox, Nick, Break, Timothy J., Oikonomou, Vasileios, Dutzan, Nicolas, Desai, Jigar V., Swidergall, Marc, Freiwald, Tilo, Chauss, Daniel, Harrison, Oliver J., Alejo, Julie, Williams, Drake W., Pittaluga, Stefania, Lee, Chyi-Chia R., Bouladoux, Nicolas, and Swamydas, Muthulekha

Published
2021

38. CXCR1-mediated neutrophil degranulation and fungal killing promote Candidaclearance and host survival

Author

Swamydas, Muthulekha, Gao, Ji-Liang, Break, Timothy J., Johnson, Melissa D., Jaeger, Martin, Rodriguez, Carlos A., Lim, Jean K., Green, Nathaniel M., Collar, Amanda L., Fischer, Brett G., Lee, Chyi-Chia Richard, Perfect, John R., Alexander, Barbara D., Kullberg, Bart-Jan, Netea, Mihai G., Murphy, Philip M., and Lionakis, Michail S.

Abstract

CXCR1 as a mediator of neutrophil fungal killing and host defense against systemic fungal infection in mice and humans.

Published
2016
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39. CD8+ T cells produce a dialyzable antigen-specific activator of dendritic cells.

Author

Myles IA, Zhao M, Nardone G, Olano LR, Reckhow JD, Saleem D, Break TJ, Lionakis MS, Myers TG, Gardina PJ, Kirkpatrick CH, Holland SM, and Datta SK

Subjects
Animals, Epitopes immunology, Humans, Immunity, Immunologic Memory, Interleukin-17 metabolism, Lymphocyte Activation immunology, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Biological, Receptors, Antigen, T-Cell metabolism, S100 Proteins metabolism, Spleen pathology, Antigens metabolism, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Dialysis
Abstract

Cellular lysates from PPD + donors have been reported to transfer tuberculin reactivity to naïve recipients, but not diphtheria reactivity, and vice versa. A historically controversial topic, the terms "transfer factor" and "DLE" were used to characterize the reactivity-transferring properties of lysates. Intrigued by these reported phenomena, we found that the cellular extract derived from antigen-specific memory CD8 + T cells induces IL-6 from antigen-matched APCs. This ultimately elicits IL-17 from bystander memory CD8 + T cells. We have identified that dialyzable peptide sequences, S100a9, and the TCR β chain from CD8 + T cells contribute to the molecular nature of this activity. We further show that extracts from antigen-targeted T cells enhance immunity to Staphylococcus aureus and Candida albicans These effects are sensitive to immunization protocols and extraction methodology in ways that may explain past discrepancies in the reproducibility of passive cellular immunity., (© Society for Leukocyte Biology.)

Published
2017
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