Effector differentiation by stem-like intraepithelial γδ T cells is required for host defense against infection

Intraepithelial γδ T cells (γδIELs) are crucial for maintaining intestinal homeostasis, yet their functional regulation remains incompletely understood. Here, we identified two distinct γδIEL subsets: CD160+TCF1+BCL6+ stem-like and granzymeB+BLIMP1+ effector-like cells; the latter exhibited cytotoxic activity. Stem-like γδIELs differentiated into effector-like cells in response to microbiota and pathogen infection. IL-12, in cooperation with IL-15 and TCR signaling, activated a STAT4-BLIMP1 pathway to induce effector differentiation, and IL-12 signaling was required for their cytotoxic function. Tcf7 deletion significantly reduced stem-like but not effector-like γδIELs, while Bcl6 deficiency increased effector-like γδIELs selectively. In contrast, the absence of Prdm1 not only abolished the development of effector-like γδIELs but also impaired the clearance of enterogenous pathogens. Taken together, these findings define two functionally distinct γδIEL subsets with a hierarchical regulatory program linking microbial signals and cytokine pathways to their cytotoxic function in the gut.