IL-21 Controls ILC3 Cytokine Production and Promotes a Protective Phenotype in a Mouse Model of Colitis

Abstract

Group 3 innate lymphoid cells (ILC3s) have dual roles in intestinal health, acting in both protective and pathogenic capacities, and importantly, modulations in this population of ILCs have been implicated in inflammatory bowel disease (IBD). Further, subpopulations of ILC3s have been described as serving specific functions in maintaining homeostasis or responding to infection, and aberrant activation of one or more of these subpopulations could exacerbate IBD. However, the signals that enforce the protective and pathogenic features of ILC3s are not fully elucidated. Here we show that IL-21, a cytokine primarily produced by CD4 T cells, acts on a subpopulation of intestinal ILC3s to promote a protective phenotype. IL-21 signaling does not affect the MHCII expressing ILC3 subset but promotes ILC3s that express Tbet and are poised to produce IL-22. Consistent with a protective phenotype, IL-21-deficiency dampens cytokine-induced IL-17A production. We show that exacerbated colitis develops in mice lacking the IL-21 receptor, in agreement with a protective role for IL-21 signaling on ILC3s. These data reveal a novel role for IL-21 in shaping ILC responses in the intestine and provide one mechanism by which effector CD4 T cells can influence innate immunity.

Single-cell sequencing reveals the evolution of immune molecules across multiple vertebrate species

“…This finding suggests that BC-1 cells represent a more primitive population and have an evolutionary connection with ectotherm B cells [80] , [81] , which is also supported by our data that BC1 cells and the corresponding enriched genes were present in all species. Moreover, the current study revealed that the unique T cell-like population identified in zebrafish (FT) displayed a strong innate immune signature enriched in lymphocyte activation and response to interferon, and expressed high levels of ID2, IL21R, IRF7, and CCR9, implying it is a group of innate-like lymphocytes as described previously in zebrafish [82] , [83] , [84] , [85] . It will be interesting to further investigate the phenotype and function of this population in future studies.…”

Impact of MyD88, Microbiota, and Location on Type 1 and Type 3 Innate Lymphoid Cells during Toxoplasma gondii Infection

“…It likely involves IL-1b, IL-15, and IL-12, based upon in vitro studies demonstrating ILC3-to-ILC1 conversion in the presence of these cytokines (33,44). It has also been demonstrated that LP ILC3 are induced to express T-bet in the presence of IL-21, a cytokine previously implicated in optimal T cell and B cell responses in chronic Toxoplasma infection (45,46).…”

Inflammatory Bowel Disease: A Review of Pre-Clinical Murine Models of Human Disease

“…A population of CD4 + IL-17F + T cells was sufficient to induce colitis in RAG1 -deficient recipients, where the transition of these precursors to Th1-like cells was an absolute requirement for disease [ 144 ]. Interestingly, IL-21 signalling was recently proposed to dampen T-cell transfer colitis by reducing IL-17A production and augmenting IL-22 production in populations of ILC3s [ 145 ].…”