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High-affinity help CD4 T cells are critical for the development of tissue-resident memory (TRM) CD8 T cells during persistent viral infection of the central nervous system with polyomavirus. Ren et al. identified a role for IL-21 produced by virus-specific high-affinity CD4 T cells in driving differentiation of brain CD8 T cells into TRM. IL21R−/− brain CD8 T cells have defects in antigen recall and oxidative metabolism and fail to differentiate into TRM.
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