25 results on '"Wakim, Linda M."'
Search Results
2. IFITM3 and type I interferons are important for the control of influenza A virus replication in murine macrophages.
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Londrigan, Sarah L., Wakim, Linda M., Smith, Jeffrey, Haverkate, Anne J., Brooks, Andrew G., and Reading, Patrick C.
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INFLUENZA A virus , *VIRAL replication , *MEMBRANE proteins , *INTERFERON receptors , *SEASONAL influenza , *VIRUS diseases , *TYPE I interferons - Abstract
Abortive infection of macrophages serves as a "dead end" for most seasonal influenza A virus (IAV) strains, and it is likely to contribute to effective host defence. Interferon (IFN)-induced transmembrane protein 3 (IFITM3) restricts the early stages of IAV replication in epithelial cells, but IFITM3 restriction of IAV replication in macrophages has not been previously investigated. Herein, macrophages isolated from IFITM3-deficient mice were more susceptible to initial IAV infection, but late-stage viral replication was still controlled through abortive infection. Strikingly, IFNα/β receptor (IFNAR)-deficient macrophages infected with IAV were not only more susceptible to initial infection, but these cells also supported productive viral replication. Significantly, we have established that abortive IAV infection in macrophages is controlled through a type I IFN-dependent mechanism, where late-stage IAV replication can proceed in the absence of type I IFN responses. These findings provide novel mechanistic insight into macrophage-specific processes that potently shut down IAV replication. • IFITM3 restricts early-stage influenza A virus infection in macrophages. • Influenza A virus replication in macrophages is limited by type I interferons. • Influenza A virus abortive macrophage infection is controlled by type I interferons. [ABSTRACT FROM AUTHOR]
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- 2020
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3. Memory T Cell Dynamics in the Lung during Influenza Virus Infection.
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Pizzolla, Angela and Wakim, Linda M.
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Influenza A virus is highly contagious, infecting 5-15% of the global population every year. It causes significant morbidity and mortality, particularly among immunocompromised and at-risk individuals. Influenza virus is constantly evolving, undergoing continuous, rapid, and unpredictable mutation, giving rise to novel viruses that can escape the humoral immunity generated by current influenza virus vaccines. Growing evidence indicates that influenza-specific T cells resident along the respiratory tract are highly effective at providing potent and rapid protection against this inhaled pathogen. As these T cells recognize fragments of the virus that are highly conserved and less prone to mutation, they have the potential to provide cross-strain protection against a wide breadth of influenza viruses, including newly emerging strains. In this review, we will discuss how influenza-specific memory T cells in the lung are established and maintained and how we can harness this knowledge to design broadly protective influenza A virus vaccines. [ABSTRACT FROM AUTHOR]
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- 2019
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4. Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3.
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Wakim, Linda M, Gupta, Nishma, Mintern, Justine D, and Villadangos, Jose A
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T cells , *TISSUES , *GENE expression , *INFLUENZA , *ANTIVIRAL agents , *INTERFERONS , *MEMBRANE proteins - Abstract
Infection with influenza virus results in the deposition of anti-influenza CD8+ resident memory T cells (TRM cells) in the lung. As a consequence of their location in the lung mucosal tissue, these cells are exposed to cytopathic pathogens over the life of the organism and may themselves be susceptible to infection. Here we found that lung TRM cells selectively maintained expression of the interferon-induced transmembrane protein IFITM3, a protein that confers broad resistance to viral infection. Lung TRM cells that lacked IFITM3 expression were more susceptible to infection than were their normal counterparts and were selectively lost during a secondary bout of infection. Thus, lung TRM cells were programmed to retain IFITM3 expression, which facilitated their survival and protection from viral infection during subsequent exposures. [ABSTRACT FROM AUTHOR]
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- 2013
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5. The Molecular Signature of Tissue Resident Memory CD8 T Cells Isolated from the Brain.
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Wakim, Linda M., Woodward-Davis, Amanda, Liu, Ruijie, Hu, Yifang, Villadangos, Jose, Smyth, Gordon, and Bevan, Michael J.
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CD8 antigen , *T cells , *TISSUES , *BIOMARKERS , *CHEMOTAXIS , *GENE expression - Abstract
Tissue resident memory (Trm) CD8 T cells represent a newly described memory T cell population. We have previously characterized a population of Trm cells that persists within the brain after acute virus infection. Although capable of providing marked protection against a subsequent local challenge, brain Trm cells do not undergo recall expansion after dissociation from the tissue. Further-more, these Trm cells do not depend on the same survival factors as the circulating memory T cell pool as assessed either in vivo or in vitro. To gain greater insight into this population of cells, we compared the gene expression profiles of Trm cells isolated from the brain with those of circulating memory T cells isolated from the spleen after an acute virus Infection. Trm cells displayed altered expression of genes involved in chemotaxis, expressed a distinct set of transcription factors, and overexpressed several Inhibitory receptors. Cumulatively, these data indicate that Trm cells are a distinct memory T cell population disconnected from the circulating memory T cell pool and display a unique molecular signature that likely results in optimal survival and function within their local environment. [ABSTRACT FROM AUTHOR]
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- 2012
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6. Cross-dressed dendritic cells drive memory CD8+ T-cell activation after viral infection.
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Wakim, Linda M. and Bevan, Michael J.
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T cells , *LYMPHOCYTES , *ANTIGENS , *ANTIGEN-antibody reactions , *IMMUNE response , *DENDRITIC cells , *VIRUS diseases - Abstract
After an infection, cytotoxic T lymphocyte precursors proliferate and become effector cells by recognizing foreign peptides in the groove of major histocompatibility complex (MHC) class I molecules expressed by antigen-presenting cells (APCs). Professional APCs specialized for T-cell activation acquire viral antigen either by becoming infected themselves (direct presentation) or by phagocytosis of infected cells, followed by transfer of antigen to the cytosol, processing and MHC class I loading in a process referred to as cross-presentation. An alternative way, referred to as 'cross-dressing', by which an uninfected APC could present antigen was postulated to be by the transfer of preformed peptide-MHC complexes from the surface of an infected cell to the APC without the need of further processing. Here we show that this mechanism exists and boosts the antiviral response of mouse memory CD8+ T cells. A number of publications have demonstrated sharing of peptide-loaded MHC molecules in vitro. Our in vitro experiments demonstrate that cross-dressing APCs do not acquire peptide-MHC complexes in the form of exosomes released by donor cells. Rather, the APCs and donor cells have to contact each other for the transfer to occur. After a viral infection, we could isolate cross-dressed APCs able to present viral antigen in vitro. Furthermore, using the diphtheria toxin system to selectively eliminate APCs that could only acquire viral peptide-MHC complexes by cross-dressing, we show that such presentation can promote the expansion of resting memory T cells. Notably, naive T cells were excluded from taking part in the response. Cross-dressing is a mechanism of antigen presentation used by dendritic cells that may have a significant role in activating previously primed CD8+ T cells. [ABSTRACT FROM AUTHOR]
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- 2011
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7. From the thymus to longevity in the periphery
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Wakim, Linda M and Bevan, Michael J
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MOLECULAR immunology , *THYMUS , *IMMUNOLOGIC memory , *T cell differentiation , *HOST-parasite relationships , *IMMUNE system - Abstract
An important attribute of the adaptive immune system is the ability to remember a prior encounter with a pathogen; an ability termed immunological memory. Bigger, better, and stronger responses are mounted upon a secondary encounter with the pathogen potentially resulting in clearance of the infection before the development of disease. We will review recent advances in the field of memory CD8+ T cell differentiation focusing on both intrinsic and extrinsic factors that govern the development of T cell memory. [Copyright &y& Elsevier]
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- 2010
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8. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.
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Gebhardt, Thomas, Wakim, Linda M, Eidsmo, Liv, Reading, Patrick C, Heath, William R, and Carbone, Francis R
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Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an example of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry. [ABSTRACT FROM AUTHOR]
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- 2009
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9. CD8+ T-cell attenuation of cutaneous herpes simplex virus infection reduces the average viral copy number of the ensuing latent infection.
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Wakim, Linda M., Jones, Claerwen M., Gebhardt, Thomas, Preston, Christopher M., and Carbone, Francis R.
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T-cell receptor genes , *HERPES simplex virus , *IMMUNE response , *VIRUS diseases , *SKIN infections - Abstract
During an initial encounter with herpes simplex virus type 1 (HSV-1) it takes several days for an adaptive immune response to develop and for herpes-specific CD8+ T cells to infiltrate sites of infection. By this time the virus has firmly established itself within the innervating sensory nervous system where it then persists indefinitely. Preventing the establishment of viral latency would require blocking the skin to nervous system transmission of the virus. We wished to examine if CD8+ T cells present early during acute HSV-1 infection could block this transmission. We show that effector CD8+ T cells failed to prevent the establishment of HSV latency even when present prior to infection. This lack of blocking likely reflects the delayed infiltration of the CD8+ T cells into the infected skin. Examination of the kinetics of HSV-1 infection highlighted the rapidity at which the virus infects the sensory ganglia and singled out early viral replication within the skin as an important factor in determining the magnitude of the ensuing latent infection. Though unable to prevent the establishment of latency, CD8+ T cells could reduce the average viral copy number of the residual latent infection by dampening the skin infection and thus limiting the skin-to-nerve transmission of virus.Immunology and Cell Biology (2008) 86, 666–675; doi:10.1038/icb.2008.47; published online 8 July 2008 [ABSTRACT FROM AUTHOR]
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- 2008
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10. Dendritic Cell—Induced Memory T Cell Activation in Nonlymphoid Tissues.
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Wakim, Linda M., Waithman, Jason, Van Rooijen, Nico, Heath, William R., and Carbone, Francis R.
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T cells , *DENDRITIC cells , *LYMPHOID tissue , *NONLYMPHOID leukemia , *HERPES simplex virus , *CYTOLOGY , *EPITHELIAL cells , *DENDRITES , *ANTIGENS - Abstract
Secondary Lymphoid organs are dominant sites of T cell activation, although many T cells are subsequently retained within peripheral tissues. Currently, these nonlymphoid compartments are viewed as sites only of effector T cell function, without the involvement of renewed induction of immunity via the interactions with professional antigen-presenting cells. We describe a method of reactivation of herpes simplex virus to examine the stimulation of tissue-resident T cells during secondary challenge. The results revealed that memory CD8+ T cell responses can be initiated within peripheral tissues through a tripartite interaction that includes CD4+ T cells and recruited dendritic cells. These findings lend evidence for the existence of a sophisticated T cell response mechanism in extra-lymphoid tissues that can act to control localized infection. [ABSTRACT FROM AUTHOR]
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- 2008
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11. When input does not match output, lung-resident memory T cells decay.
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Wakim, Linda M
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T cells , *TUMOR necrosis factors , *INFLUENZA viruses , *PNEUMONIA , *PATHOGENIC microorganisms - Abstract
The article discusses the tissue-resident memory CD8+ T cells (Trm). Topics discussed include maintenance of lung Trm pool by Influenza viral antigen, identification of tumor necrosis factor-α within the lung inflammatory profile and development of vaccination strategies for providing long-term protection against inhaled pathogen.
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- 2017
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12. Vaccine-induced inflammation and inflammatory monocytes promote CD4+ T cell-dependent immunity against murine salmonellosis.
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Wang, Nancy, Scott, Timothy A., Kupz, Andreas, Shreenivas, Meghanashree M., Peres, Newton G., Hocking, Dianna M., Yang, Chenying, Jebeli, Leila, Beattie, Lynette, Groom, Joanna R., Pierce, Thomas P., Wakim, Linda M., Bedoui, Sammy, and Strugnell, Richard A.
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T cells , *SALMONELLA diseases , *MONOCYTES , *VACCINE effectiveness , *IMMUNITY , *ANTIGEN presentation - Abstract
Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80–90%) against lethal murine salmonellosis, in comparison with a moderately protective (40–50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity. Author summary: Salmonella enterica infections exemplify the immunological challenges posed by intracellular bacterial pathogens, for which there are often limited or no effective vaccines and antimicrobial resistance is rapidly on the rise. A common signature among these infections is a strong dependence on CD4+ T cell responses for host immunity, although how such responses can be effectively induced in a vaccine setting remains a key challenge. Using two live-attenuated vaccines that offer distinct levels of protection against lethal salmonellosis in a murine model, we investigated what properties of vaccine-induced immune responses can be targeted for improving vaccine efficacy. Our data show that the longevity of activated CD4+ T cells in lymphoid and non-lymphoid organs is closely linked with vaccine efficacy. At the cellular level, we have shown that CD11b+Ly6GnegLy6Chi inflammatory monocytes play an important role in stimulating antigen-specific CD4+ T cells through antigen presentation mechanisms, as well as the production of CXCL9 and IL-12. Since our data suggest that acute inflammation is beneficial for optimising vaccine-induced T cell immunity, considerations should be given to preserving the targets of inflammatory signalling pathways as a means for improving vaccine efficacy in future development. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Mouse Mx1 Inhibits Herpes Simplex Virus Type 1 Genomic Replication and Late Gene Expression In Vitro and Prevents Lesion Formation in the Mouse Zosteriform Model.
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Tessema, Melkamu B., Farrukee, Rubaiyea, Andoniou, Christopher E., Degli-Esposti, Mariapia A., Oates, Clare V., Barnes, James B., Wakim, Linda M., Brooks, Andrew G., Londrigan, Sarah L., and Reading, Patrick C.
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HUMAN herpesvirus 1 , *HERPES simplex virus , *GENE expression , *INFLUENZA , *HERPESVIRUS diseases , *LABORATORY mice , *DORSAL root ganglia , *ANIMAL disease models - Abstract
Myxovirus resistance (Mx) proteins are dynamin-like GTPases that are inducible by interferons (IFNs) following virus infections. Most studies investigating Mx proteins have focused on their activity against influenza A viruses (IAV), although emerging evidence suggests that some Mx proteins may exhibit broader antiviral activity. Herein, we demonstrate that in addition to IAV, overexpression of mouse Mx1 (mMx1), but not mMx2, resulted in potent inhibition of growth of the human alphaherpesviruses herpes simplex virus 1 (HSV-1) and HSV-2, whereas neither inhibited the mouse betaherpesvirus murine cytomegalovirus (MCMV) in vitro. IFN induction of a functional endogenous mMx1 in primary mouse fibroblasts ex vivo was also associated with inhibition of HSV-1 growth. Using an in vitro overexpression approach, we demonstrate that mutations that result in redistribution of mMx1 from the nucleus to the cytoplasm or in loss of its combined GTP binding and GTPase activity also abrogated its ability to inhibit HSV-1 growth. Overexpressed mMx1 did not inhibit early HSV-1 gene expression but was shown to inhibit both replication of the HSV-1 genome as well as subsequent late gene expression. In a mouse model of cutaneous HSV-1 infection, mice expressing a functional endogenous mMx1 showed significant reductions in the severity of skin lesions as well as reduced HSV-1 titers in both the skin and dorsal root ganglia (DRG). Together, these data demonstrate that mMx1 mediates potent antiviral activity against human alphaherpesviruses by blocking replication of the viral genome and subsequent steps in virus replication. Moreover, endogenous mMx1 potently inhibited pathogenesis in the zosteriform mouse model of HSV-1 infection. IMPORTANCE While a number of studies have demonstrated that human Mx proteins can inhibit particular herpesviruses in vitro, we are the first to report the antiviral activity of mouse Mx1 (mMx1) against alphaherpesviruses both in vitro and in vivo. We demonstrate that both overexpressed mMx1 and endogenous mMx1 potently restrict HSV-1 growth in vitro. mMx1-mediated inhibition of HSV-1 was not associated with inhibition of virus entry and/or import of the viral genome into the nucleus, but rather with inhibition of HSV-1 genomic replication as well as subsequent late gene expression. Therefore, inhibition of human alphaherpesviruses by mMx1 occurs by a mechanism that is distinct from that reported for human Mx proteins against herpesviruses. Importantly, we also provide evidence that expression of a functional endogenous mMx1 can limit HSV-1 pathogenesis in a mouse model of infection. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Staphylococcus aureus specific lung resident memory CD4+ Th1 cells attenuate the severity of influenza virus induced secondary bacterial pneumonia.
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Braverman, Jessica, Monk, Ian R., Ge, Chenghao, Westall, Glen P., Stinear, Timothy P., and Wakim, Linda M.
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- 2022
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15. Influenza, but not SARS‐CoV‐2, infection induces a rapid interferon response that wanes with age and diminished tissue‐resident memory CD8+ T cells.
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Nguyen, Thi HO, McAuley, Julie L, Kim, Youry, Zheng, Ming ZM, Gherardin, Nicholas A, Godfrey, Dale I, Purcell, Damian FJ, Sullivan, Lucy C, Westall, Glen P, Reading, Patrick C, Kedzierska, Katherine, and Wakim, Linda M
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T cells , *SARS-CoV-2 , *TYPE I interferons , *INFLUENZA , *OLDER people - Abstract
Older individuals exhibit a diminished ability to respond to and clear respiratory pathogens and, as such, experience a higher rate of lung infections with a higher mortality rate. It is unclear why respiratory pathogens impact older people disproportionately. Using human lung tissue from donors aged 22–68 years, we assessed how the immune cell landscape in lungs changes throughout life and investigated how these immune cells respond following in vitro exposure to influenza virus and SARS‐CoV‐2, two clinically relevant respiratory viruses. While the frequency of most immune cell subsets profiled in the human lung remained stable with age, memory CD8+ T cells declined, with the tissue‐resident memory (Trm) CD8+ T‐cell subset being most susceptible to age‐associated attrition. Infection of lung tissue with influenza virus resulted in an age‐associated attenuation in the antiviral immune response, with aged donors producing less type I interferon (IFN), GM‐CSF and IFNγ, the latter correlated with a reduction of IFNγ‐producing memory CD8+ T cells. In contrast, irrespective of donor age, exposure of human lung cells to SARS‐CoV‐2, a pathogen for which all donors were immunologically naïve, did not trigger activation of local immune cells and did not result in the induction of an early IFN response. Our findings show that the attrition of tissue‐bound pathogen‐specific Trm in the lung that occurs with advanced age, or their absence in immunologically naïve individuals, results in a diminished early antiviral immune response which creates a window of opportunity for respiratory pathogens to gain a greater foothold. [ABSTRACT FROM AUTHOR]
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- 2021
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16. RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells.
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Tullett, Kirsteen M., Tan, Peck Szee, Hae-Young Park, Schittenhelm, Ralf B., Michael, Nicole, Rong Li, Policheni, Antonia N., Gruber, Emily, Cheng Huang, Fulcher, Alex J., Danne, Jillian C., Czabotar, Peter E., Wakim, Linda M., Mintern, Justine D., Ramm, Georg, Radford, Kristen J., Caminschi, Irina, O'Keeffe, Meredith, Villadangos, Jose A., and Wright, Mark D.
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ANTIGEN receptors , *DENDRITIC cells , *UBIQUITIN ligases , *PROTEOLYSIS , *CELL receptors , *ANTIGEN presentation - Abstract
The dendritic cell receptor Clec9A facilitates processing of dead cell-derived antigens for cross-presentation and the induction of effective CD8+ T cell immune responses. Here, we show that this process is regulated by E3 ubiquitin ligase RNF41 and define a new ubiquitin-mediated mechanism for regulation of Clec9A, reflecting the unique properties of Clec9A as a receptor specialized for delivery of antigens for cross-presentation. We reveal RNF41 is a negative regulator of Clec9A and the cross-presentation of dead cell-derived antigens by mouse dendritic cells. Intriguingly, RNF41 regulates the downstream fate of Clec9A by directly binding and ubiquitinating the extracellular domains of Clec9A. At steady-state, RNF41 ubiquitination of Clec9A facilitates interactions with ER-associated proteins and degradation machinery to control Clec9A levels. However, Clec9A interactions are altered following dead cell uptake to favor antigen presentation. These findings provide important insights into antigen cross-presentation and have implications for development of approaches to modulate immune responses. [ABSTRACT FROM AUTHOR]
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- 2020
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17. Suboptimal SARS-CoV-2−specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype.
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Habel, Jennifer R., Nguyen, Thi H. O., van de Sandt, Carolien E., Juno, Jennifer A., Chaurasia, Priyanka, Wragg, Kathleen, Koutsakos, Marios, Hensen, Luca, Xiaoxiao Jia, Brendon Chu, Wuji Zhang, Hyon-Xhi Tan, Flanagan, Katie L., Doolan, Denise L., Torresi, Joseph, Weisan Chen, Wakim, Linda M., Cheng, Allen C., Doherty, Peter C., and Petersen, Jan
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T cells , *COVID-19 - Abstract
An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2−specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLAA* 02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/ S269–277 and A2/Orf1ab3183–3191. Using peptide−HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/ Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cellswere detected at comparable frequencies (∼1.3 × 10−5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10−6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein–Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10−4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19. [ABSTRACT FROM AUTHOR]
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- 2020
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18. Neutrophils play an ongoing role in preventing bacterial pneumonia by blocking the dissemination of Staphylococcus aureus from the upper to the lower airways.
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Ge, Chenghao, Monk, Ian R, Monard, Sarah C, Bedford, James G, Braverman, Jessica, Stinear, Timothy P, and Wakim, Linda M
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NEUTROPHILS , *PNEUMONIA , *NASAL cavity , *INTRODUCED species , *POPULATION , *RHINITIS , *HUMAN metapneumovirus infection , *STREPTOCOCCUS pneumoniae - Abstract
Staphylococcus aureus is found in the nasal cavity of up to 30% of the human population. Persistent nasal carriage of S. aureus is a risk factor for influenza virus‐induced secondary bacterial pneumonia. There is limited understanding of the factors that cause S. aureus to shift from the upper to the lower respiratory tract and convert from a commensal organism to an invasive pathogen. Here we show that neutrophils actively prevent S. aureus dissemination. Establishment of a mouse model of localized S. aureus nasal carriage revealed variations in the longevity of persistence of S. aureus isolates. Improved persistence within this site was associated with reduced nasal inflammation, less neutrophil egress into the airways and reduced neutrophil–bacteria association. Neutrophil depletion of mice with localized S. aureus nasal carriage triggered the development of an invasive S. aureus infection. Moreover, utilizing a model of influenza‐induced staphylococcal pneumonia we showed that treatment with granulocyte–colony‐stimulating factor, a potent enhancer of neutrophil number and function, significantly reduced bacterial loads in the lung and improved disease outcomes. These data reveal that neutrophils play an important and active role in confining S. aureus to the upper respiratory tract and highlight the use of approaches that improve neutrophil function as effective strategies to attenuate morbidity associated with staphylococcal pneumonia. [ABSTRACT FROM AUTHOR]
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- 2020
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19. Zymosan by-passes the requirement for pulmonary antigen encounter in lung tissue-resident memory CD8+ T cell development.
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Caminschi, Irina, Lahoud, Mireille H., Pizzolla, Angela, and Wakim, Linda M.
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- 2019
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20. Rapid interferon independent expression of IFITM3 following T cell activation protects cells from influenza virus infection.
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Bedford, James G., O’Keeffe, Meredith, Reading, Patrick C., and Wakim, Linda M.
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T cells , *INTERFERONS , *INFLUENZA viruses , *ANTIVIRAL agents , *MEMBRANE proteins - Abstract
Interferon-induced transmembrane protein 3 (IFITM3) is a potent antiviral protein that enhances cellular resistance to a variety of pathogens, including influenza virus. Classically defined as an interferon-stimulated gene, expression of IFITM3 on cells is rapidly up-regulated in response to type I and II interferon. Here we found that IFITM3 is rapidly up-regulated by T cells following their activation and this occurred independently of type I and II interferon and the interferon regulatory factors 3 and 7. Up-regulation of IFITM3 on effector T cells protected these cells from virus infection and imparted a survival advantage at sites of virus infection. Our results show that IFITM3 expression on effector T cells is crucial for these cells to mediate their effector function and highlights an interferon independent pathway for the induction of IFITM3 which, if targeted, could be an effective approach to harness the activity of IFITM3 for infection prevention. [ABSTRACT FROM AUTHOR]
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- 2019
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21. Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles.
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Pizzolla, Angela, Nguyen, Thi Ho, Sant, Sneha, Jaffar, Jade, Loudovaris, Tom, Mannering, Stuart I, Thomas, Paul G, Westall, Glen P, Kedzierska, Katherine, and Wakim, Linda M
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CELL differentiation , *CELL physiology , *CELL receptors , *COMPARATIVE studies , *IMMUNITY , *INFLUENZA , *LUNGS , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *RESPIRATORY infections , *T cells , *PHENOTYPES , *EVALUATION research , *MONONUCLEAR leukocytes - Abstract
The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8+ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific CD8+ Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of CD8+ Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus-specific CD8+ T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific CD8+ T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza-specific CD8+ Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other CD8+ T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants. [ABSTRACT FROM AUTHOR]
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- 2018
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22. Nasal-associated lymphoid tissues (NALTs) support the recall but not priming of influenza virus-specific cytotoxic T cells.
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Pizzolla, Angela, Zhongfang Wang, Groom, Joanna R., Kedzierska, Katherine, Brooks, Andrew G., Reading, Patrick C., and Wakim, Linda M.
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LYMPHOID tissue , *INFLUENZA viruses , *CYTOTOXIC T cells , *RESPIRATORY infections , *CHEMOKINES - Abstract
The lymphoid tissue that drains the upper respiratory tract represents an important induction site for cytotoxic T lymphocyte (CTL) immunity to airborne pathogens and intranasal vaccines. Here, we investigated the role of the nasal-associated lymphoid tissues (NALTs), which are mucosal-associated lymphoid organs embedded in the submucosa of the nasal passage, in the initial priming and recall expansion of CD8+ T cells following an upper respiratory tract infection with a pathogenic influenza virus and immunization with a live attenuated influenza virus vaccine. Whereas NALTs served as the induction site for the recall expansion of memory CD8+ T cells following influenza virus infection or vaccination, they failed to support activation of naïve CD8+ T cells. Strikingly, NALTs, unlike other lymphoid tissues, were not routinely surveyed during the steady state by circulating T cells. The selective recruitment of memory T cells into these lymphoid structures occurred in response to infection-induced elevation of the chemokine CXCL10, which attracted CXCR3+ memory CD8+ T cells. These results have significant implications for intranasal vaccines, which deliver antigen to mucosal-associated lymphoid tissue and aim to elicit protective CTL-mediated immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
23. Respiratory DC Use IFITM3 to Avoid Direct Viral Infection and Safeguard Virus-Specific CD8+ T Cell Priming.
- Author
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Infusini, Giuseppe, Smith, Jeffrey M., Yuan, He, Pizzolla, Angela, Ng, Wy Ching, Londrigan, Sarah L., Haque, Ashraful, Reading, Patrick C., Villadangos, Jose A., and Wakim, Linda M.
- Subjects
- *
DENDRITIC cells , *INFLUENZA diagnosis , *CD80 antigen , *T cells , *IMMUNE response , *VIRAL antigens , *THERAPEUTICS - Abstract
Respiratory dendritic cells (DC) play a pivotal role in the initiation of adaptive immune responses to influenza virus. To do this, respiratory DCs must ferry viral antigen from the lung to the draining lymph node without becoming infected and perishing en route. We show that respiratory DCs up-regulate the expression of the antiviral molecule, interferon-induced transmembrane protein 3 (IFITM3) in response to influenza virus infection, in a manner dependent on type I interferon signaling and the transcription factors IRF7 and IRF3. Failure of respiratory DCs to up-regulate IFITM3 following influenza virus infection resulted in impaired trafficking to the draining LN and consequently in impaired priming of an influenza-specific CD8+ T cell response. The impaired trafficking of IFITM3-deficient DC correlated with an increased susceptibility of these DC to influenza virus infection. This work shows that the expression of IFITM3 protects respiratory DCs from influenza virus infection, permitting migration from lung to LN and optimal priming of a virus specific T-cell response. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
24. Endogenous Murine BST-2/Tetherin Is Not a Major Restriction Factor of Influenza A Virus Infection.
- Author
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Londrigan, Sarah L., Tate, Michelle D., Job, Emma R., Moffat, Jessica M., Wakim, Linda M., Gonelli, Christopher A., Purcell, Damien F. J., Brooks, Andrew G., Villadangos, Jose A., Reading, Patrick C., and Mintern, Justine D.
- Subjects
- *
INFLUENZA A virus , *VIRUS diseases , *CELL membranes , *MACROPHAGES , *DISEASE susceptibility - Abstract
BST-2 (tetherin, CD317, HM1.24) restricts virus growth by tethering enveloped viruses to the cell surface. The role of BST-2 during influenza A virus infection (IAV) is controversial. Here, we assessed the capacity of endogenous BST-2 to restrict IAV in primary murine cells. IAV infection increased BST-2 surface expression by primary macrophages, but not alveolar epithelial cells (AEC). BST-2-deficient AEC and macrophages displayed no difference in susceptibility to IAV infection relative to wild type cells. Furthermore, BST-2 played little role in infectious IAV release from either AEC or macrophages. To examine BST-2 during IAV infection in vivo, we infected BST-2-deficient mice. No difference in weight loss or in viral loads in the lungs and/or nasal tissues were detected between BST-2-deficient and wild type animals. This study rules out a major role for endogenous BST-2 in modulating IAV in the mouse model of infection. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
25. Epidermal Viral Immunity Induced by CD8α[sup+]Dendritic Cells But Notj by Langerhans Cells.
- Author
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Allan, Rhys S., Smith, Chris M., Beiz, Gabrielle T., Lint, Allison L van, Wakim, Linda M., Heath, William R., and Carbone, Francis R.
- Subjects
- *
DENDRITIC cells , *LANGERHANS cells , *T cells , *LYMPH nodes , *EPIDERMIS - Abstract
The classical paradigm for dendritic cell function derives from the study of Langerhans cells, which predominate within skin epidermis. After an encounter with foreign agents, Langerhans cells are thought to migrate to draining lymph nodes, where they initiate T cell priming. Contrary to this, we show here that infection of murine epidermis by herpes simplex virus did not result in the priming of virus-specific cytotoxic T lymphocytes by Langerhans cells. Rather, the priming response required a distinct CD8α[sup+] dendritic cell subset. Thus, the traditional view of Langerhans cells in epidermal immunity needs to be revisited to accommodate a requirement for other dendritic cells in this response. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
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