Tfh-cell-derived interleukin 21 sustains effector CD8⁺ T cell responses during chronic viral infection

CD4⁺ T cell-derived interleukin 21 (IL-21) sustains CD8⁺ T cell responses during chronic viral infection, but the helper subset that confers this protection remains unclear. Here, we applied scRNA and ATAC-seq approaches to determine the heterogeneity of IL-21⁺CD4⁺ T cells during LCMV clone 13 infection. CD4⁺ T cells were comprised of three transcriptionally and epigenetically distinct populations: Cxcr6⁺ Th1 cells, Cxcr5⁺ Tfh cells, and a previously unrecognized Slamf6⁺ memory-like (Tml) subset. T cell differentiation was specifically redirected toward the Tml subset during chronic, but not acute, LCMV infection. Although this subset displayed an enhanced capacity to accumulate and some developmental plasticity, it remained largely quiescent, which may hinder its helper potential. Conversely, mixed bone marrow chimera experiments revealed that Tfh cell-derived IL-21 was critical to sustain CD8⁺ T cell responses and viral control. Thus, strategies that bolster IL-21⁺Tfh cell responses may prove effective in enhancing CD8⁺ T cell-mediated immunity.