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. CD4 T cell–deficient mice had similar defects in gene expression related to TRM development, but intrathecal delivery of IL-21 reversed these deficiencies. These results provide critical insight into the role of IL-21 production by high-affinity CD4 T cells in driving differentiation of brain TRM during persistent viral infection.
Development of tissue-resident memory (TRM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5hi PD-1hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R−/−) fail to become bTRM. IL-21+ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R−/− brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack TRM core signature genes. CD4 T cell–deficient and IL21R−/− brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell–depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5hi PD-1hi CD4 T cells in the brain produce IL-21, which drives CD8 bTRM differentiation in response to a persistent viral infection.
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