A central feature of the intestinal mucosal immune system is the ability enable antigen specific tolerance to the plethora of gut bacteria that coat its surface. Genetic variants in TNFSF15 (which encodes the protein TL1A) are linked to inflammatory bowel disease and have implicated roles for TL1A in regulating both T cell and innate lymphoid cells (ILC), but how these cellular pathways coordinate a response to limit intestinal inflammation is not completely understood. Deletion of TL1A receptor Tnfrsf25 (also called DR3), we demonstrate that TL1A signaling is required for efficient generation of RORγt/Foxp3⁺ intestinal iTregs at steady state. To investigate if this response resulted from DR3 deletion in T cells or the potential role for DR3 signaling in ILCs to regulate iTregs indirectly, we generated antigen specific transgenic T cells to H. Hepaticus (Hh) with DR3 deletion. Our results reveal that TL1A signaling is dispensable on T cells but required on group 3 ILCs (ILC3s) to regulate the balance between intestinal iTreg and inflammatory Th17 cells. RNA sequencing of ILC3s revealed the specific induction of Bhlhe40 in response to TL1A stimulation. Using conditional deletion models, we defined Bhlhe40 as a transcriptional regulator of ILC3 expression of Tnfsf4 (OX40L) and the subsequent requirement for ILC3-specific Bhlhe40 and Tnfsf4 in promoting Hh-specific Treg induction. Furthermore, Bhlhe40 is required for microbe induced-ILC3 production of GM-CSF, which has been reported to regulate microbe-induced recruitment of CX3CR1⁺ macrophages. Selective depletion of CX3CR1⁺ macrophage promoted Hh-specific Th17 induction and inhibited Hh-specific Treg differentiation. These data reveal a novel function for TL1A and the downstream transcription factor Bhlhe40 in enabling ILC3 coordination of gut commensal T cell immunity.

Brian Edelson

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