Work

BATF3 controls the homeostatic maintenance and function of innate-like γδ T cells

Year: 2025

Type: preprint

Abstract: γδ T cells compose an evolutionarily conserved lineage of lymphocytes, with both adaptive- and innate-like characteristics, contributing to tissue homeostasis, immune surveillance, and rapid responses to stress and infection. While their functional diversity and tissue-specific roles are tightly regulated by transcriptional networks, the underlying molecular mechanisms remain incompletely understood. The transcription factor basic leucine zipper ATF-like transcription factor 3 (BATF3) plays a central role in the development of conventional type 1 dendritic cells (cDC1s). Here, we unveil BATF3 as a critical cell-intrinsic regulator of the homeostasis, functional specialization, and tissue distribution of γδ T cells. Batf3 -deficient mice display an altered composition of γδ T cell subsets, with a marked decrease in the numbers of innate-like γδ T cells across multiple organs when compared to their wild-type counterparts, independently of cDC1s. Loss of BATF3 impacts not only cell survival but also IL-17 production after γδ T cells complete their thymic development. Mechanistically, Batf3 -deficient innate-like γδ T cells exhibit transcriptional changes that disrupt pathways governing actin cytoskeleton remodelling, immunological synapse organization and cellular identity. Notably, Batf3 -deficient mice present decreased survival in a viral infection model highly dependent on innate-like γδ T cells. Together, our findings uncover a previously unrecognized BATF3-dependent pathway that controls γδ T cell morphology and function, profoundly impacting their biology.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2025.12.16.694583