scholarly journals Licensed NK Cell Responses to Acute Viral Infection Shape Priming and Differentiation of CD8+ T cells

2016 ◽  
Author(s):  
Jeffrey Teoh
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cell Responses ◽  
Acute Viral Infection

scholarly journals Interferon-γ acts directly on CD8+ T cells to increase their abundance during virus infection

2005 ◽  
Vol 201 (7) ◽  
pp. 1053-1059 ◽  
Author(s):  
Jason K. Whitmire ◽  
Joyce T. Tan ◽  
J. Lindsay Whitton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Interferon Γ ◽  
Current Evidence ◽  
Cell Responses ◽  
Acute Viral Infection

Interferon-γ (IFNγ) is important in regulating the adaptive immune response, and most current evidence suggests that it exerts a negative (proapoptotic) effect on CD8+ T cell responses. We have developed a novel technique of dual adoptive transfer, which allowed us to precisely compare, in normal mice, the in vivo antiviral responses of two T cell populations that differ only in their expression of the IFNγ receptor. We use this technique to show that, contrary to expectations, IFNγ strongly stimulates the development of CD8+ T cell responses during an acute viral infection. The stimulatory effect is abrogated in T cells lacking the IFNγ receptor, indicating that the cytokine acts directly upon CD8+ T cells to increase their abundance during acute viral infection.

scholarly journals Selective dependence on IL-7 for antigen-specific CD8 T cell responses during airway influenza infection

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Abdalla Sheikh ◽  
Jennie Jackson ◽  
Hanjoo Brian Shim ◽  
Clement Yau ◽  
Jung Hee Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Mediastinal Lymph Node ◽  
Influenza Infection ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Deficient Mice

AbstractInterleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. How IL-7 shapes CD8 T cell responses during an acute viral infection is less understood. We had previously shown that IL-7 signaling deficient mice have reduced accumulation of influenza-specific CD8 T cells following influenza infection. We sought to determine whether IL-7 affects early CD8 T cell expansion in the mediastinal lymph node and effector function in the lungs. Using IL-7Rα signaling deficient mice, we show that IL-7 is required for a normal sized mediastinal lymph node and the early clonal expansion of influenza-specific CD8 T cells therein. We show that IL-7 plays a cell-intrinsic role in the accumulation of NP366–374 and PA224–233-specific CD8 T cells in the lymph node. We also found that IL-7 shapes terminal differentiation, degranulation and cytokine production to a greater extent in PA224–233-specific than NP366–374-specific CD8 T cells. We further demonstrate that IL-7 is induced in the lung tissue by viral infection and we characterize multiple cellular sources that contribute to IL-7 production. Our findings on IL-7 and its effects on lower respiratory diseases will be important for expanding the utility of therapeutics that are currently available.

scholarly journals Programmed Death 1 Regulates Development of Central Memory CD8 T Cells after Acute Viral Infection

2011 ◽  
Vol 186 (11) ◽  
pp. 6280-6286 ◽  
Author(s):  
S. Rameeza Allie ◽  
Weijun Zhang ◽  
Shinchiro Fuse ◽  
Edward J. Usherwood
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Central Memory ◽  
Memory Cd8 T Cells ◽  
Acute Viral Infection ◽  
Programmed Death ◽  
Programmed Death 1

scholarly journals 314 NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A338-A338
Author(s):  
Berengere Salome ◽  
John Sfakianos ◽  
Andrew Charap ◽  
Adam Farkas ◽  
Daniel Geanon ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Bladder Tumors ◽  
Cell Responses

BackgroundBladder cancer is characterized by a poor prognosis, with muscle-invasive cases harboring a 34–76% 10-year recurrence-free survival rate.1 Neoadjuvant PD-1/PD-L1 blockade strategies have recently been approved by the US Food and Drug Administration for bladder cancer treatment, yet only achieving a complete response rate of 31–37%, thereby suggesting additional mechanisms of resistance.2 HLA-E is a known inhibitor of NKG2A+ CD8 T cells and NK cell responses. A monoclonal antibody binding to the NKG2A receptor has been developed and proven to restore CD8 T cell and NK cell responses in head and neck cancer, with ongoing clinical trials across multiple tumor indications.3 4 We evaluated the potential role of the HLA-E/NKG2A inhibitory pathway in modulating T cell immunity in bladder cancer.MethodsCyTOF was performed on CD8+ T cells from fresh bladder tumors (n=6), as well as on expanded CD8+ T cells from bladder-draining lymph nodes (n=11) and tumors (n=8). Flow cytometry (n=25) and single-cell RNA-sequencing (scRNAseq) (n=13) were performed on cells from fresh bladder tumors.ResultsMechanisms of tumor escape from CD8+ T cell recognition include impairment of antigen presentation. Accordingly, we found a significant reduction of HLA class I expression on tumors. However, expression of DNAM-1-activating ligands (e.g. CD112,CD155) on bladder tumors was retained, indicating a possible role for TCR-independent activation pathways traditionally ascribed to natural killer (NK) cells. Using mass cytometry and scRNAseq, we observed that acquisition of NKG2A on tumor-derived PD-1+ CD8+ T cells promotes tissue-resident memory features alongside diminished CD28 expression and significantly weaker sensitivity to CD3/CD28-signaling. However, NKG2A+ CD8 T cells possess a proliferative advantage with enhanced expression of DNAM-1 and cytolytic machinery.Strikingly, we found that NKG2A+PD-1+ CD8 T cells are strongly activated in response to HLA class I-deficient tumors compared to their NKG2A- PD-1+ CD8 T cell counterparts. TCR-independent NK-like function by NKG2A+ CD8 T cell is partly mediated by the DNAM-1 pathway and inhibited by HLA-E. NKG2A+ CD8 T cell functions are restored upon NKG2A blockade, where efficiency positively correlates with HLA-E expression on bladder tumors.ConclusionsCollectively, our data indicate that NKG2A+ CD8 T cells display a strong capacity for TCR-independent activation that enables them to circumvent bladder tumor evasion mechanisms. NKG2A+ CD8 T cells lack expression of CD28 suggesting a lower susceptibility to PD-1-mediated inhibiton. Our data suggest a need for thorough reappraisal of current protocols that assess CD8 T cell exhaustion and for strategies to restore their antitumor functions.ReferencesSanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, Lotan Y. Bladder cancer. Nat Rev Dis Primers 2017 April 13;3:17022. doi: 10.1038/nrdp.2017.22. PMID: 28406148. Rouanne M, Bajorin DF, Hannan R, Galsky MD, Williams SB, Necchi A, Sharma P, Powles T. Rationale and outcomes for neoadjuvant immunotherapy in urothelial carcinoma of the bladder. Eur Urol Oncol 2020 December;3(6):728–738. doi: 10.1016/j.euo.2020.06.009. Epub 2020 Nov 8. PMID: 33177001. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Bléry M, Bonnafous C, Gauthier L, Morel A, Rossi B, Remark R, Breso V, Bonnet E, Habif G, Guia S, Lalanne AI, Hoffmann C, Lantz O, Fayette J, Boyer-Chammard A, Zerbib R, Dodion P, Ghadially H, Jure-Kunkel M, Morel Y, Herbst R, Narni-Mancinelli E, Cohen RB, Vivier E. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK Cells. Cell 2018 December 13;175(7):1731–1743.e13. doi: 10.1016/j.cell.2018.10.014. Epub 2018 Nov 29. PMID: 30503213; PMCID: PMC6292840. van Hall T, André P, Horowitz A, Ruan DF, Borst L, Zerbib R, Narni-Mancinelli E, van der Burg SH, Vivier E. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J Immunother Cancer 2019 October 17;7(1):263. doi: 10.1186/s40425-019-0761-3. PMID: 31623687; PMCID: PMC6798508.

scholarly journals A Role for Perforin in Downregulating T-Cell Responses during Chronic Viral Infection

1999 ◽  
Vol 73 (3) ◽  
pp. 2527-2536 ◽  
Author(s):  
Mehrdad Matloubian ◽  
M. Suresh ◽  
Alison Glass ◽  
Marisa Galvan ◽  
Kit Chow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Chronic Viral Infection ◽  
Persistently Infected ◽  
Cell Responses ◽  
Immune Mediated ◽  
Lcmv Infection

ABSTRACT Cytotoxic T cells secrete perforin to kill virus-infected cells. In this study we show that perforin also plays a role in immune regulation. Perforin-deficient (perf −/−) mice chronically infected with lymphocytic choriomeningitis virus (LCMV) contained greater numbers of antiviral T cells compared to persistently infected +/+ mice. The enhanced expansion was seen in both CD4 and CD8 T cells, but the most striking difference was in the numbers of LCMV-specific CD8 T cells present in infected perf −/− mice. Persistent LCMV infection of +/+ mice results in both deletion and anergy of antigen-specific CD8 T cells, and our results show that this peripheral “exhaustion” of activated CD8 T cells occurred less efficiently in perf −/− mice. This excessive accumulation of activated CD8 T cells resulted in immune-mediated damage in persistently infected perf −/− mice; ∼50% of these mice died within 2 to 4 weeks, and mortality was fully reversed by in vivo depletion of CD8 T cells. This finding highlights an interesting dichotomy between the role of perforin in viral clearance and immunopathology; perforin-deficient CD8 T cells were unable to clear the LCMV infection but were capable of causing immune-mediated damage. Finally, this study shows that perforin also plays a role in regulating T-cell-mediated autoimmunity. Mice that were deficient in both perforin and Fas exhibited a striking acceleration of the spontaneous lymphoproliferative disease seen in Fas-deficient (lpr) mice. Taken together, these results show that the perforin-mediated pathway is involved in downregulating T-cell responses during chronic viral infection and autoimmunity and that perforin and Fas act independently as negative regulators of activated T cells.

Natural Killer Cell Licensing Delineates NK “Helper/Repair” and NK “Effector/Suppressor” Subsets During Viral Infections

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 13-13
Author(s):  
Can M. Sungur ◽  
Anthony E. Zamora ◽  
Ethan G. Aguilar ◽  
Yajarayma Tang-Feldman ◽  
Juan Du ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Viral Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Subset ◽  
Gm Csf ◽  
Cell Responses ◽  
Late Stages

Abstract Natural killer (NK) cells are innate lymphocytes with anti-viral and anti-tumor capabilities that can be divided into subsets based on differential receptor expression patterns. NK cells that express inhibitory receptors that can bind to the MHC class I molecules present in the host are considered to be “licensed,” fully functional NK cells with normal production of cytokines and cytotoxicity in response to targets. In contrast, “unlicensed” NK cells are unable to strongly bind to host MHC class I molecules and are in turn hyporesponsive to targets in terms of cytotoxicity and cytokine production. Recent data suggest that NK cells also regulate antigen-specific adaptive immune responses during the course of viral infection, playing a significant role in viral clearance and immunopathology. The specific populations of NK cells that may mediate these differential effects during the course of viral infection have not been identified. Here, we demonstrate differential effector and immunoregulatory functions of licensed versus unlicensed NK cells during influenza and murine cytomegalovirus (MCMV) infections in mouse models. We hypothesize that licensed NK cells serve a dual role as both effector and suppressor populations depending on the stage of viral infection. Similarly, unlicensed NK cells serve a dual role as helper and repair populations during the early and late stages of viral infection, respectively. We performed licensed and unlicensed NK cell subset depletions and then infected mice with influenza or MCMV and ascertained effects on: viral titers, antigen-specific T cell responses, and tissue pathology. Our data show that after influenza or MCMV infection, there is a significant reduction in antigen-specific CD4+ and CD8+ T cell populations in the presence of licensed NK cells as determined by tetramer-positive cells. Targeting of these T cells by the NK “effector/suppressor” licensed population appears later in the time course of infection and to be through NKG2D recognition and perforin-mediated lysis based on upregulation of NKG2D ligands Rae-1 and MULT1 on the T cells and the loss of T cell regulation with NKG2D blockade or perforin knockout mice. Depletion of the unlicensed NK “helper/repair” subset reduced the number of DCs in the lymph nodes and reduced total antigen-specific T cells. The unlicensed NK cells were found to home to the lymph node and produce increased levels of GM-CSF early during infection resulting in DC expansion. Additionally, the unlicensed NK cells are the primary producers of IL-22 based on intracellular staining in the damaged tissues in the late stages of viral infection, aiding in tissue regeneration. Adoptive transfer of unlicensed NK cells with IL-22 silencing through siRNA transfection into immunodeficient mice showed increased tissue damage and pathology as compared to transfer of non-IL-22 silenced NK cells. Collectively, these data suggest differential roles of licensed versus unlicensed NK cells that are both tissue and time-specific. At early stages of infection, licensed NK cells serve as direct anti-viral cells at the sites of infection while unlicensed cells promote DC expansion in the lymph nodes promoting antigen-specific T cell responses. Conversely, at the late stages of infection, licensed NK cells serve an immunoregulatory role by lysing antigen-specific T cells at the site of infection and in the lymph nodes, while unlicensed NK cells travel to the sites of injury to aid in tissue repair through production of IL-22. Importantly, a similar functional polarization of resting human NK cells was also observed after PMA/ionomycin stimulation, with a small population of unlicensed NK cells producing IL-22 and a bias towards GM-CSF secretion over IFNγ production by the unlicensed NK cell subset. We conclude that licensed NK cells have an effector/suppressor function while the unlicensed NK cells function as the helper/repair population suggesting distinct roles of NK cell subsets throughout the course of infection. By understanding the functions and characteristics of these NK cell populations, specific subsets can either by adoptively transferred or therapeutically targeted clinically to aid in different stages of immunological response including elimination of the virus, inhibiting the adaptive immune response, or aiding in tissue repair and regeneration. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A262 DIFFERENTIAL PHENOTYPES AND LOCALIZATION OF CD8+ T CELL RESPONSES TO ACUTE AND CHRONIC ENTERIC VIRAL INFECTION

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 139-140
Author(s):  
B K Hardman ◽  
L C Osborne
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Post Infection ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses

Abstract Background Human Norovirus infection is the most common viral cause of gastroenteritis globally and the second most reported viral infection in Canada after the common cold. Most infections are acute, symptomatic, and rapidly cleared but some cases persist asymptomatically or induce post-infectious irritable bowel syndrome. Despite the global burden of these infections, no vaccine to prevent disease exists nor is the mechanism for persistence understood. MNV-CW3 and MNV-CR6 are murine noroviruses which demonstrate distinct biological behaviors that correlate with differential quantity and quality of antiviral CD8+ T cell responses. MNV-CW3 causes acute systemic infections initiated in the small intestine and cleared by day 8 due to a robust antiviral CD8+ T cell response. In contrast, MNV-CR6 causes chronic infections localized to the colonic intestinal epithelium and induces fewer antiviral CD8+ T cells with reduced effector molecule expression. Aims This research interrogates the mechanisms underlying strain-specific differential antiviral CD8+ T cell responses. Methods At days 3, 4, 5 and 8 post-infection, the phenotype and quantity of adoptively transferred MNV specific CD8+ T cells in the spleen, mesenteric lymph node (MLN), and the small and large intestine are analyzed by flow cytometry. Concurrently, immunofluorescent microscopy is used to determine whether CD8+ T cells are broadly disseminated throughout the intestines or localize in acute clusters of antiviral response. Combining these complementary techniques provides novel insight into mechanisms governing intestinal antiviral T cell responses. Results Activated MNV-specific CD8 T cells first accumulate in the MLN following oral infection with both MNV-CW3 and CR6, suggesting this is the site of immune activation. Supporting this hypothesis, preliminary data indicates that preventing T cell egress from activation sites by treatment with the S1PR1 agonist FTY720 leads to an enrichment of activated CD8+ T cells in the MLN following CW3 infection. Notably, the earliest stages of CD8+ T cell activation to CR6 infection is delayed compared to that elicited by CW3. Furthermore, at the peak of CD8+ T cell expansion (day 8 post-infection), CR6-elicited CD8+ T cells preferentially develop into short-lived effector populations rather than memory precursor populations. Conclusions These data reveal previously unknown differences in early events in CD8+ T cell activation following infection with two highly related viral strains that correlate with long-lasting effects on T cell differentiation and function. We are currently investigating the hypothesis that MNV-CW3 and CR6 may induce activation of distinct populations of, or pathways in, APC populations that would drive these differences. These results may have broad impacts on our understanding of how non-latent, chronic viral infections persist within a host. Funding Agencies CIHR

Maintenance of CD8+T Cells during Acute Viral Infection of the Central Nervous System Requires CD4+T Cells But Not Interleukin-2

2005 ◽  
Vol 18 (1) ◽  
pp. 162-169 ◽  
Author(s):  
Jiehao Zhou ◽  
David R. Hinton ◽  
Stephen A. Stohlman ◽  
Chih-Pin Liu ◽  
Lingwen Zhong ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Acute Viral Infection ◽  
The Central Nervous System
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