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

TCRγδ⁺ intraepithelial lymphocytes (γδIELs) are crucial for maintaining intestinal homeostasis, yet their functional regulation remains incompletely understood. Here, we demonstrated two distinct γδIEL subsets: CD160⁺TCF1⁺BCL6⁺ stem-like and granzymeB⁺BLIMP1⁺ effector-like cells, with the latter exhibiting cytotoxic activity. Stem-like γδIELs differentiated into effector-like cells in response to microbiota and pathogen infection. Interleukin 12 (IL-12), in cooperation with IL-15 and T cell receptor (TCR) signaling, activated a STAT4-BLIMP1 pathway to induce effector differentiation, while IL-12 signaling was required for their cytotoxic function. TCF1 transcription factor deletion reduced stem-like but not effector-like γδIELs, while BCL6 deficiency increased effector-like γδIELs selectively. By contrast, the absence of the transcription factor BLIMP1 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 and cytokine signals to cytotoxic γδT cell function in the gut.