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bioRxiv · 10.64898/2025.12.16.694583

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

Papotto, P. H.·Hernandez-Garcia, E.·Zarco-Cuadrillero, A.·Redondo-Urzainqui, A.·Parkinson, J. E.·Pinheiro, R. G. R.·MacDonald, A.·Sancho, D.·Silva-Santos, B.·Allen, J. E.·Hayday, A. C.·Iborra, S.·Munoz-Ruiz, M.
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Abstract

{gamma}{delta} 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 {gamma}{delta} T cells. Batf3-deficient mice display an altered composition of {gamma}{delta} T cell subsets, with a marked decrease in the numbers of innate-like {gamma}{delta} 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 {gamma}{delta} T cells complete their thymic development. Mechanistically, Batf3-deficient innate-like {gamma}{delta} 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 {gamma}{delta} T cells. Together, our findings uncover a previously unrecognized BATF3-dependent pathway that controls {gamma}{delta} T cell morphology and function, profoundly impacting their biology.

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Papotto, P. H., Hernandez-Garcia, E., Zarco-Cuadrillero, A., Redondo-Urzainqui, A., Parkinson, J. E., Pinheiro, R. G. R., MacDonald, A., Sancho, D., Silva-Santos, B., Allen, J. E., Hayday, A. C., Iborra, S., Munoz-Ruiz, M.. 2025-12-18. BATF3 controls the homeostatic maintenance and function of innate-like γδ T cells. https://doi.org/10.64898/2025.12.16.694583

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