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

Abstract

<p id="P2">Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked <i>TNFSF15</i> 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. </p><p id="P3">Microbial-induced TL1A regulates the innate and adaptive functions of ILC3 in colitis</p><p id="P4">Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. <span style="text-decoration: underline">Castellanos</span> 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. </p><p class="first" id="P5"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/3459ce3e-46cc-4999-af6f-a4537c015977/PubMedCentral/image/nihms-1510430-f0008.jpg"/> </div> </p>