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

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.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2025-12-18
DOI
https://doi.org/10.64898/2025.12.16.694583
Primary Topic
T-cell and B-cell Immunology
Type
article
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article

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

Elena Hernández‐García, Pedro Henrique Papotto, Miguel Muñoz‐Ruiz, James E Parkinson et al.
bioRxiv (Cold Spring Harbor Laboratory)
T-cell and B-cell Immunology
article

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

Elena Hernández‐García, Pedro Henrique Papotto, Miguel Muñoz‐Ruiz, James E Parkinson, Bruno Silva‐Santos, Rúben G. R. Pinheiro, David Sancho, Andrew S. MacDonald, Ana Redondo‐Urzainqui, Salvador Iborra, Adrian Hayday, Judith E. Allen, Ángela Zarco-Cuadrillero
article en

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.

bioRxiv (Cold Spring Harbor Laboratory)
Universidad Complutense de Madrid (ES), King's College London (GB), University of Manchester (GB), Instituto Nacional de Investigaciones Nucleares (MX), Inmunotek (Spain) (ES), Centre for Immunity, Infection and Evolution (GB), Institute of Immunology (HR), Centro Nacional de Investigaciones Científicas (CU), Geographic Information Management (Belgium) (BE), Centro de Investigaciones Cardiovasculares (AR), University of Edinburgh (GB)
Wellcome Trust, Comunidad de Madrid, University of Manchester, European Commission, Centro Nacional de Investigaciones Cardiovasculares, Fundación Fero, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, Medical Research Council, Agencia Estatal de Investigación
Openalex Percentile: Top 54%
T-cell and B-cell Immunology
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