The Regulation and Maturation of Antiviral Immune Responses

Whitton, J. Lindsay; Liu, Fei; Nussbaum, Alexander K.; Whitmire, Jason K.

doi:10.1016/s0065-3527(04)63003-x

Cited by 20 publications

(26 citation statements)

References 258 publications

(231 reference statements)

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“…ϩ T cell responses (9)(10)(11) and provides an ideal system to examine innate and adaptive CD8 ϩ T cell functions (5,10,12). Virus-specific T cells are readily identified using peptide-major histocompatibility complex (MHC) tetramer reagents, making it possible to monitor the responses of T cells with defined antigenic specificity at various stages of infection.…”

Section: Lymphocytic Choriomeningitis Virus (Lcmv) Infection Of Mice mentioning

confidence: 99%

Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8⁺T Cell Functions

Freeman

Meyer

2014

J Virol

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Virus-specific CD8؉ T cells provide classical adaptive immunity by responding to cognate peptide antigen, but they may also act in an "innate" capacity by responding directly to cytokine stimulation. Here, we examined regulation of these distinct T cell functions by anti-inflammatory cytokines (interleukin-4 [IL-4], IL-10, and transforming growth factor ␤ [TGF-␤]). Innate gamma interferon (IFN-␥) production by CD8؉ T cells following exposure to IL-12 plus IL-18, IL-12 plus tumor necrosis factor alpha (TNF-␣), or IL-12 plus IL-15 was inhibited by exposure to anti-inflammatory cytokines either before or shortly after stimulation. However, inhibition was not universal, as other activation parameters, including upregulation of CD25 and CD69, remained largely unaltered. In contrast, peptide-specific T cell responses were resistant to inhibition by anti-inflammatory cytokines. This was not due to downregulation of cytokine receptor expression or an inability to signal through cytokine receptors since phosphorylation of STAT proteins remained intact. These results highlight key differences in cytokine-mediated regulation of innate and adaptive T cell functions, which may help balance effective antiviral immune responses while reducing T cell-mediated immunopathology. IMPORTANCE This study demonstrates key differences between the regulation of "innate" and "adaptive" CD8 ؉ T cell functions following activation by innate cytokines or viral peptide. Innate production of IFN-␥ by CD8؉ T cells following exposure to IL-12 plus IL-18, IL-12 plus TNF-␣, or IL-12 plus IL-15 was inhibited by exposure to anti-inflammatory cytokines (IL-4, IL-10, and TGF-␤). However, inhibition was not universal, as other activation parameters, including upregulation of CD25 and CD69, remained largely unaltered. In contrast, peptide-specific T cell responses were resistant to inhibition by anti-inflammatory cytokines. This distinct regulation of innate and adaptive T cell functions may serve to reduce T cell-mediated immunopathology while still allowing for effective antiviral responses at a site of infection. C D8ϩ T cells play a critical role in the control and clearance of many viral infections through the release of antiviral cytokines and lysis of infected cells. During the course of acute viral infection, antigen-specific T cells monitor their local microenvironment and in addition to responding to cognate antigen through the T cell receptor (TCR), antigen-experienced effector and memory CD8 ϩ T cells can function in a non-antigen-specific, "innate" capacity by responding directly to cytokines (1-5). This allows virus-specific CD8 ϩ T cells to act as "sentinels" and respond to subsequent, unrelated infections, even when their specific cognate antigen may not be present. In this manner, "bystander activation" of CD8 ϩ T cells can play a role in the early control of bacterial infections and confer innate protection (2, 6, 7). However, nonspecific cytokine-induced T cell activation may also contribute to immunopathology. For example, e...

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Section: Lymphocytic Choriomeningitis Virus (Lcmv) Infection Of Mice mentioning

confidence: 99%

Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8⁺T Cell Functions

Freeman

Meyer

2014

J Virol

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“…For some viruses, CD4 ϩ T cells control infection in part through their direct cytotoxic activity or by secreting antiviral cytokines (5,10,23,27,72,73). Although adoptive transfer of WNV-primed CD4 ϩ T cells significantly improved the survival of CD4…”

Section: Effector Cd4mentioning

confidence: 99%

CD4⁺T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous System

Sitati¹,

Diamond

2006

J Virol

210

190

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Although studies have established that innate and adaptive immune responses are important in controlling West Nile virus (WNV) infection, the function of CD4؉ T lymphocytes in modulating viral pathogenesis is less well characterized. Using a mouse model, we examined the role of CD4 ؉ T cells in coordinating protection against WNV infection. A genetic or acquired deficiency of CD4 ؉ T cells resulted in a protracted WNV infection in the central nervous system (CNS) that culminated in uniform lethality by 50 days after infection. Mice surviving past day 10 had high-level persistent WNV infection in the CNS compared to wild-type mice, even 45 days following infection. The absence of CD4 ؉ T-cell help did not affect the kinetics of WNV infection in the spleen and serum, suggesting a role for CD4-independent clearance mechanisms in peripheral tissues. WNVspecific immunoglobulin M (IgM) levels were similar to those of wild-type mice in CD4-deficient mice early during infection but dropped ϳ20-fold at day 15 postinfection, whereas IgG levels in CD4-deficient mice were ϳ100-to 1,000-fold lower than in wild-type mice throughout the course of infection. WNV-specific CD8 ؉ T-cell activation and trafficking to the CNS were unaffected by the absence of CD4؉ T cells at day 9 postinfection but were markedly compromised at day 15. Our experiments suggest that the dominant protective role of CD4 ؉ T cells during primary WNV infection is to provide help for antibody responses and sustain WNV-specific CD8 ؉

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“…It is generally agreed that T-cell immunity is critical for recovery from primary viral infections [53 ], but the relative role of pre-existing T-cell-and B-cell-mediated immunity during re-exposure to a specific pathogen remains an area of intense deliberation -although many are coming to realize that pre-existing antibody may play a more important role than previously realized. In terms of primary vaccinia infections, T-cell-mediated immunity is very important; when an HIV þ military recruit almost died of disseminated vaccinia following smallpox vaccination in 1984, it was probably due to low T-cell immunity [54].…”

Section: Duration and Mechanisms Of Protective Immunitymentioning

confidence: 99%

Immunological memory to viral infection

Slifka¹

2004

Current Opinion in Immunology

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The Regulation and Maturation of Antiviral Immune Responses

Cited by 20 publications

References 258 publications

Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8⁺T Cell Functions

Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8⁺T Cell Functions

CD4⁺T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous System

Immunological memory to viral infection

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The Regulation and Maturation of Antiviral Immune Responses

Cited by 20 publications

References 258 publications

Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8+T Cell Functions

Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8+T Cell Functions

CD4+T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous System

Immunological memory to viral infection

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Product

Resources

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Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8⁺T Cell Functions

Anti-Inflammatory Cytokines Directly Inhibit Innate but Not Adaptive CD8⁺T Cell Functions

CD4⁺T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous System