IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection

Development of tissue-resident memory (T-RM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5(hi) PD-1(hi) CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R(-/-)) fail to become bT(RM). 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 T-RM 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 CXCR5(hi) PD-1(hi) CD4 T cells in the brain produce IL-21, which drives CD8 bT(RM) differentiation in response to a persistent viral infection.