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

Abstract

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.

Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion

“…However, the comprehensive scale of scATAC-seq cell types enabled the discovery of novel patterns. For example, variant-enhancers associated with systemic sclerosis showed high accessibility in mature NK cells and pDCs, and variant-enhancers associated with ulcerative colitis showed high accessibility in mDCs and monocytes, consistent with the suggested impact of these cell types in murine models of each disease 28,29 . Additional diseases with high variant-enhancer signals in myeloid cells included a number of metabolic traits and diseases, such as fasting glucose and HDL cholesterol levels, and Type 2 diabetes, suggesting that cell-specific enhancers nominate regulatory roles for immune cells in these processes as well.…”

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…An independent study demonstrated that splenic but not intestinal MHC‐II‐expressing ILC3s can be activated through microbiota‐derived IL‐1β to express co‐stimulator molecules and thus drive CD4 + T‐cell and B‐cell responses in vivo . Similarly, microbiota‐derived signals during colitis induced the expression of the co‐stimulatory molecule OX40 on MHC‐II‐expressing ILC3s, which could subsequently activate intestinal T‐cells . ILC3s were also shown to localize within the MLN to the interface between the T‐ and B‐cell zone to regulate T follicular helper cell (Tfh)‐dependent germinal centre reactions .…”

“…63 Similarly, microbiota-derived signals during colitis induced the expression of the co-stimulatory molecule OX40 on MHC-II-expressing ILC3s, which could subsequently activate intestinal T-cells. 64 ILC3s were also shown to localize within the MLN to the interface between the T-and B-cell zone to regulate T follicular helper cell (Tfh)-dependent germinal centre reactions. 65 This was dependent on MHC-II expression and antigen presentation by ILC3s and significantly reduced colonic IgA + B-cell responses to commensal microbiota, thereby contributing to hostÀcommensal mutualism.…”

The balance of power: innate lymphoid cells in tissue inflammation and repair

“…This homeostatic IL-22 induction, even in the absence of overt disease, helps to limit inflammatory colitis and has been correlated with mucosal healing in inflammatory bowel disease (IBD) (83,84). Production of IBD-associated TNF-like ligand 1A (TL1A) by intestinal mononuclear phagocytes is a central regulator of ILC3 production of IL-22 and mediates protection during acute colitis (85). Similarly, ILC3-dependent protection occurs at other mucosal sites, including the lung, where commensal-dependent ILC3s protect against Streptococcus pneumoniae (86) and promote oropharyngeal barrier defense through IL-17 and IL-22 (87).…”

“…Under an inflammatory microenvironment such as IBD, these regulatory mechanisms are reduced (138,141). Moreover, increased TL1A, which is highly expressed by MNPs in IBD, can induce robust expression of the costimulatory molecule OX40L on MHC II + ILC3s and drive colonic T cell-dependent inflammation (85). Additional studies are needed to elucidate the contribution of ILC3s to mucosal T cell immunity and their potential role as therapeutic targets.…”