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.