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

Abstract

CD4 T cell localization impacts function and differentiation. Beura et al. show that memory CD4 ⁺ T cells are largely resident in both lymphoid and non-lymphoid tissues, organize local recall responses, and share overlapping transcriptional and location-specific features with CD8 ⁺ T _RM.

Abstract

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.

Graphical Abstract