Mucosal-Associated Invariant T Cell Features and TCR Repertoire Characteristics During the Course of Multiple Sclerosis.

Edgar Carnero Contentti,Mauricio F Farez,Jorge Correale

doi:10.3389/fimmu.2019.02690

Abstract

Objective: To investigate the frequency, phenotype, function, and longitudinal repertoire of mucosal-associated invariant T (MAIT) cells in relapsing remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) patients.Methods: Forty-five RRMS patients in remission, 20 RRMS patients experiencing exacerbations, 15 PPMS patients, and 30 healthy controls (HCs) were included in the study. MAIT cells were identified phenotypically as CD3+ TCRγδ− Vα7.2 + CD161high. In 15 patients, MAIT cell number and MRI lesions were evaluated every 6 months, for 36 months. MAIT cell TCRVβ repertoire was defined using single-cell cloning and mRNA sequencing.Results: Circulating MAIT cells were significantly reduced in both RRMS and PPMS patients, particularly during exacerbations, compared to healthy subjects. This decrease was accompanied by pro-inflammatory cytokine production (TNF-α, IFN-γ, IL-17, and GM-CSF). Three months post-exacerbation, peripheral blood MAIT cell percentages increased significantly along with clinical recovery. Likewise, we observed inverse correlation between MRI lesions and peripheral blood MAIT cell numbers. In paired samples, MAIT cell percentage was significantly higher in CSF than in peripheral blood, suggesting MAIT cell migration through the blood–brain barrier. Finally, MAIT cells showed limited TCRVβ repertoires, in both CSF and peripheral blood, which remained stable over time.Conclusions: MAIT cell levels correlated with MS course both clinically and radiologically, showing marked and sustained oligoclonality. These findings may contribute to a better understanding of pathophysiological phenomena underlying the course of MS, and discovery of MAIT cell inhibitors could pave the way for the development of new therapeutic strategies.

Highlights

The etiology of multiple sclerosis (MS) remains elusive, it is known that environmental factors and susceptible genes are involved in disease pathogenesis, with immunological, genetic, and histopathology studies of MS patients showing that autoimmunity plays a key role [1,2,3]
mucosal-associated invariant T (MAIT) cells were defined as CD3+CD4−TCRγ/δ−TRAV1-2+CD161high (Figure 1A)
remitting MS in remission (RRMS) patients in remission or experiencing exacerbations had significantly lower absolute MAIT cell numbers compared to HCs [16.22 ± 8.38 vs. 57.23 ± 23.05 cells/μl (p < 0.0001), and 5.28 ± 3.65 vs. 57.23 ± 23.05 cells/μl (p < 0.0001), respectively; Figure 1C]

Summary

Introduction

The etiology of multiple sclerosis (MS) remains elusive, it is known that environmental factors and susceptible genes are involved in disease pathogenesis, with immunological, genetic, and histopathology studies of MS patients showing that autoimmunity plays a key role [1,2,3]. MAIT cells display a restricted αβ T cell receptor (TCR), in which the TCRVα chain comprises a canonical Vα7.2-Jα33 ( on the IMGT denomination will be used: TRAV1-2-TRAJ33) rearrangement, paired with a limited number of TCRβ chains: TRBV20-1, TRBV6-1, TRBV64, TRBV6-5, and TRBV-13 [7, 8], and less frequent usage of the non-canonical TRAV1-2-TRAJ12/20 TCR rearrangement [8, 9]. They can be identified by staining for TRAV1-2 and either CD161, or IL-18Rα, in the TCRγδ−CD4−CD3+ compartment [10]. These data expand the function of MR1 beyond the presentation of microbial antigens, indicating that MR1-restricted cells can participate in the development of different inflammatory processes

Methods

Results

Conclusion