Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes.

Teruyuki Sano,Victoria Fang,Carlos Serafin Martinez,Susan R Schwab,Charles Ng,Oleksandra Gorshko,Jhimmy Talbot,Yi Yang,Reina Kurakake,Alessandra Chen,Ivan Cabrera,Takahiro Kageyama,Ranit Kedmi,Dan R Littman

doi:10.1016/j.celrep.2021.109608

Abstract

Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here, we show that intestine-draining mesenteric lymph nodes (MLNs), not intestine proper, are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their upregulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLNs and accumulation of the cells in the lamina propria.

Highlights

CD4+ T helper cells play crucial roles in vertebrate adaptive immune responses against potentially pathogenic microbes
We previously demonstrated that mono-colonization of germ-free mice with commensal segmented filamentous bacteria (SFB) is sufficient to induce T helper 17 (Th17) cells that are specific for Segmented filamentous bacteria (SFB) antigens (Ivanov et al, 2009; Yang et al, 2014)
To monitor when, where, and how naive T cells differentiate into Th17 cells upon SFB colonization, we adoptively transferred carboxyfluorescein succinimidyl ester (CFSE)-labeled naive T cells from SFB-specific T cell antigen receptor (TCR) transgenic (7B8) mice into SFB-gavaged host mice (Yang et al, 2014)

Summary

Introduction

CD4+ T helper cells play crucial roles in vertebrate adaptive immune responses against potentially pathogenic microbes. CD4+ T cells respond to antigens encoded by commensal microbes and thereby contribute to the diversity of the T cell antigen receptor (TCR) repertoire resident within tissues. Differentiation of T cells into effector cells with diverse programs requires their activation through the TCR and CD28, the co-stimulatory receptor, as well as signaling through a multitude of cytokine receptors. Cytokines in the microenvironment, produced in large part by myeloid cells, direct the different programs of differentiation, which are readily distinguished by the induction of subset-specific transcription factors. Induced regulatory T cells (iTreg) upregulate Foxp (and often other lineage-defining transcription factors, e.g., RORgt) and can produce IL-10 (Sefik et al, 2015; Ohnmacht et al, 2015; Xu et al, 2018)

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Conclusion