A Critical Role for Mucosal-Associated Invariant T Cells as Regulators and Therapeutic Targets in Systemic Lupus Erythematosus.

Goh Murayama,Hitoshi Suzuki,Yusuke Suzuki,Shinji Nakamura,Sachiko Hirose,Taiga Kuga,Sachiko Miyake,Naoto Tamura,Ken Yamaji,Hirofumi Amano,Atsushi Nomura,Asako Chiba,Tomohiro Mizuno

doi:10.3389/fimmu.2019.02681

Goh Murayama, Hitoshi Suzuki + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2019.02681

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Abstract

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like lymphocytes that are restricted by major histocompatibility complex-related molecule 1 (MR1). In this study, we investigated the role of MAIT cells in the pathogenesis of lupus in FcγRIIb−/−Yaa mice, a spontaneous animal model of lupus. Using two approaches of MAIT cell deficiency, MR1 knockout animals and a newly synthesized inhibitory MR1 ligand, we demonstrate that MAIT cells augment the disease course of lupus by enhancing autoantibody production and tissue inflammation. MR1 deficiency reduced germinal center responses and T cell responses in these mice. Suppression of MAIT cell activation by the inhibitory MR1 ligand reduced autoantibody production and lupus nephritis in FcγRIIb−/−Yaa mice. MAIT cells directly enhanced autoantibody production by B cells in vitro. Our results indicate the contribution of MAIT cells to lupus pathology and the potential of these cells as novel therapeutic targets for autoimmune diseases such as lupus.

Highlights

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T lymphocytes restricted by major histocompatibility complex-related molecule 1 (MR1) [1] and display innate-like properties
By crossing FcγRIIb−/−Yaa mice [21], a spontaneous lupus mouse model, to MR1-deficient mice that lack MAIT cells, the current study demonstrates that MAIT cell deficiency results in reduced disease severity, as shown by decreased autoantibody production and lower glomerulonephritis scores, and that these effects are accompanied by reduced germinal center responses as well as reduced T cell and innate T cell responses in MR1-deficient lupus mice
MAIT cells constituted a high proportion of glomerular CD3+ cells (Figure 1C, Supplementary Table 1)

Summary

Introduction

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T lymphocytes restricted by major histocompatibility complex-related molecule 1 (MR1) [1] and display innate-like properties. The majority of MR1-restricted MAIT cells express the semi-invariant T cell receptor (TCR) α chain Vα7.2-Jα33 in humans and Vα19-Jα33 in mice. MAIT cells recognize non-peptide antigens presented by the non-polymorphic MR1 molecules that include microbially-derived vitamin B2 (riboflavin) derivatives with MAIT cell-activating activity and vitamin B9 (folic acid) derivatives that are non-activating [4]. Similar to other innate lymphocytes, including invariant natural killer T (iNKT) cells, MAIT cells respond very rapidly upon activation by TCR signaling or cytokine stimulation in the absence of exogenous antigens [5,6,7,8].

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