Gut environment-induced intraepithelial autoreactive CD4(+) T cells suppress central nervous system autoimmunity via LAG-3.

Atsushi Kadowaki,Takashi Yamamura,Asako Chiba,Hideki Mochizuki,Ryoko Saga,Sachiko Miyake

doi:10.1038/ncomms11639

Abstract

The gut environment has been found to significantly influence autoimmune diseases such as multiple sclerosis; however, immune cell mechanisms are unclear. Here we show that the gut epithelium of myelin oligodendrocyte glycoprotein(35-55)-specific T-cell receptor transgenic mice contains environmental stimuli-induced intraepithelial lymphocytes (IELs) that inhibit experimental autoimmune encephalomyelitis on transfer. These cells express surface markers phenotypical of ‘induced' IELs, have a TH17-like profile and infiltrate the central nervous system (CNS). They constitutively express Ctla4 and Tgfb1 and markedly upregulate Lag3 expression in the CNS, thereby inhibiting inflammation. We also demonstrate the suppressive capability of CD4+ IELs with alternative antigen specificities, their proliferation in response to gut-derived antigens and contribution of the microbiota and dietary aryl hydrocarbon receptor ligands to their induction. Thus, the gut environment favours the generation of autoreactive CD4+ T cells with unique regulatory functions, potentially important for preventing CNS autoimmunity.

Highlights

The gut environment has been found to significantly influence autoimmune diseases such as multiple sclerosis; immune cell mechanisms are unclear
Our initial question was whether Myelin oligodendrocyte glycoprotein (MOG)(35-55)-reactive T-cell receptor (TCR)-transgenic mice (2D2) would harbour intraepithelial lymphocytes (IELs) in the intestinal mucosa, even though the large majority of CD4 þ T cells express Va3.2 and Vb11 TCR chains
2D2-IEL-THIGH cells ameliorates the development of EAE, we examined the proliferative responses and cytokine production of draining lymph node cells at the site of immunization using MOG(35-55)-immunized WT mice that received either 2D2-IEL-THIGH cells or control cells (WT spleen cells)

Summary

Introduction

The gut environment has been found to significantly influence autoimmune diseases such as multiple sclerosis; immune cell mechanisms are unclear. We reveal that two distinct populations of T cells expressing MOG-specific TCR (2D2-TCR) are abundant in the small intestinal epithelium of 2D2 mice These cells have either low or high expression of 2D2-TCR and a phenotype of CD2 À CD5 À ‘natural’ intraepithelial lymphocytes (IELs) or CD2 þ CD5 þ ‘induced’ IELs, according to the definition by Cheroutre et al.[16] Natural IELs acquire an activated phenotype during thymic development in the presence of self-antigens, whereas induced IELs are derived from conventional T cells and acquire their activated phenotype and functionally differentiate post-thymically in response to cognate antigens. It remains unclear whether they have the potential to regulate autoimmune diseases in extraintestinal organs

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Conclusion