CD4 resident memory T cells dominate immunosurveillance and orchestrate local recall responses.

This study examines the extent to which memory CD4 T cells share immunosurveillance strategies with CD8 resident memory T cells (T). After acute viral infection, memory CD4 T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8 T cells. In contrast, memory CD4 T cells were more likely to be resident within lymphoid organs than CD8 T cells. Migration properties of memory-phenotype CD4 T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4 and CD8 T shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property-specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4 T reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4 T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8 T cells.