T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to proapoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM derepression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates.
BATF represses BIM to sustain tolerant T cells in the periphery
Disclosures: D.L. Mueller reported personal fees from AH Capital Management, LLC and personal fees from Chroma Medicine, Inc. outside the submitted work. No other disclosures were reported.
- Award Id(s): P01 AI35296,T32 AI007313
Philip J. Titcombe, Milagros Silva Morales, Na Zhang, Daniel L. Mueller; BATF represses BIM to sustain tolerant T cells in the periphery. J Exp Med 4 December 2023; 220 (12): e20230183. doi: https://doi.org/10.1084/jem.20230183
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