Microbiota-Induced TNF-like Ligand 1A Drives Group 3 Innate Lymphoid Cell-Mediated Barrier Protection and Intestinal T Cell Activation during Colitis

Jim G. Castellanos, Viola Woo, Monica Viladomiu, Gregory Putzel, Svetlana Lima, Gretchen E. Diehl, Andrew R. Marderstein, Jorge Gandara, Alexendar R. Perez, David R. Withers, Stephan R. Targan, David Q. Shih, Ellen J. Scherl, Randy S. Longman

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1077-1089.e5
JournalImmunity
Volume49
Issue number6
DOIs
StatePublished - 18 Dec 2018
Externally publishedYes

Keywords

  • CX CR1 mononuclear phagocytes
  • Crohn's disease
  • Inflammatory bowel disease
  • TL1A
  • innate lymphoid cell

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