CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis.
CD4 T cell activation during peripheral infections not only is essential in inducing protective CD8 T cell memory but also promotes CD8 T cell function and survival. However, the contributions of CD4 T cell help to antiviral CD8 T cell immunity during central nervous system (CNS) infection are not well established. Encephalitis induced by the sublethal coronavirus JHMV was used to identify when CD4 T cells regulate CD8 T cell responses following CNS infection. Peripheral expansion of virus-specific CD8 T cells was impaired when CD4 T cells were ablated prior to infection but not at 4 days postinfection. Delayed CD4 T cell depletion abrogated CD4 T cell recruitment to the CNS but only slightly diminished CD8 T cell recruitment. Nevertheless, the absence of CNS CD4 T cells was associated with reduced gamma interferon (IFN-γ) and granzyme B expression by infiltrating CD8 T cells, increased CD8 T cell apoptosis, and impaired control of infectious virus. CD4 T cell depletion subsequent to CD4 T cell CNS migration restored CD8 T cell activity and virus control. Analysis of γc-dependent cytokine expression indicated interleukin-21 (IL-21) as a primary candidate optimizing CD8 T cell activity within the CNS. These results demonstrate that CD4 T cells play critical roles in both enhancing peripheral activation of CD8 T cells and prolonging their antiviral function within the CNS. The data highlight the necessity for temporally and spatially distinct CD4 T cell helper functions in sustaining CD8 T cell activity during CNS infection.
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Timothy W
TW
Phares
Stephen A
SA
Stohlman
Mihyun
M
Hwang
Booki
B
Min
David R
DR
Hinton
Cornelia C
CC
Bergmann
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002494:Central Nervous System Infections / Q000276:immunology / Q000821:virology; D018352:Coronavirus Infections / Q000276:immunology* / Q000821:virology; D018792:Encephalitis, Viral / Q000276:immunology* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D006517:Murine hepatitis virus / Q000276:immunology / Q000502:physiology*