Microbiota-induced TNF-like ligand 1A drives group 3 innate lymphoid cell-mediated barrier protection and intestinal T cell activation during colitis

SUMMARY

Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked TNFSF15 polymorphisms and its protein TNF-like ligand 1A (TL1A) with IBD, but the functional role of TL1A is not known. Here, we found that adherent IBD-associated microbiota induced TL1A release from CX3CR1 ⁺ mononuclear phagocytes (MNPs). Using cell- specific genetic deletion models, we identified an essential role for CX3CR1 ⁺MNP- derived TL1A in driving group 3 innate lymphoid cell (ILC3) production of interleukin 22 and mucosal healing during acute colitis. In contrast to this protective role in acute colitis, TL1A-dependent expression of co-stimulatory molecule OX40L in MHCII ⁺ ILC3s during colitis led to co-stimulation of antigen-specific T cells that was required for chronic T cell colitis. These results identify a role for ILC3s in activating intestinal T cells and reveal a central role for TL1A in promoting ILC3 barrier immunity during colitis.

One Sentence Summary:

Microbial-induced TL1A regulates the innate and adaptive functions of ILC3 in colitis

eTOC/In Brief

Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Castellanos et al. show a protective role for microbial induction of the IBD-linked protein TL1A in promoting ILC3 barrier immunity and uncover a pathogenic role for TL1A-induced expression of OX40L on ILC3s in driving chronic T cell colitis.

Abstract