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(RM)). 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(RM) 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(RM) 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.