Human MAIT Cell Response Shows Subset Diversity in Multiple Sclerosis (P2.2-089)

Abstract

Objective: To investigate cytotoxic activity heterogeneity in MAIT cell populations from MS patients

Background: MAIT cells are a subset of innate T lymphocytes characterized by expression of an invariant TCR α-chain (Vα7.2-Jα33) paired with a limited number of Vβ chains. They recognize riboflavin metabolites from a range of microbes presented by MR1, a MHC-class 1-related molecule. We recently demonstrated how MAIT cell presence correlated with MS disease activity. The association recently described between MS development and the microbiome, also make MAIT cells a potentially interesting therapeutic target.

Design/Methods: Forty peripheral blood MAIT cell clones isolated from 12 relapsing remitting MS patients were studied. TCRα and β-chains were characterized using high-throughput RNA sequencing. TCCs were stimulated with 5-OE-RU, 5-OP-RU (both riboflavin derivatives), as well as with E. Coli, or Candida albicans. Cytotoxicity was measured by fatal assay, and granzyme B and perforin by ELISA. Flow cytometry was used to detect activation markers CD25 and CD69 and the degranulation marker, CD107a.

Results: MR1-restricted MAIT cells with particular TCRβ-chains reacted specifically with different types of riboflavin metabolite-derived antigens. Higher cytotoxicity magnitude and sensitivity were found for non-pathogenic E. Coli, compared to the opportunistic fungal pathogen C. albicans. MAIT cells expressing Vβ8 and Vβ13.6 were hyporesponsive to E. Coli, expressing fewer activation markers and showing less cytotoxic effect compared to MAIT cell clusters expressing different Vβ chains. Interestingly, MAIT cell response to C. albicans presented a Vβ bias, in which Vβ 13.2 MAIT cells displayed higher cytotoxic activity.

Conclusions: 1) MAIT cells display microbe-specific cytotoxic responses, indicating functional heterogeneity, despite the highly conserved nature of MR1; 2) MAIT cell TCR Vβ-chain activity influences response to specific MR1-presented antigens; 3) MAIT cell repertoire may expand depending on their response to microbial challenge, ultimately influencing the course of MS.

Disclosure: Dr. Correale has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Argentina, Teva Argentina, Novartis Argentina and MERCK Argentina, and Merck/Serono Argentina and Novartis Argentina. Dr. Carnero Contentti has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen-Idec, Genzyme, Merck-Serono, Novartis, Teva, Roche and Bayer. Dr. Farez has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with TEVA, Merck-Serono, Biogen-Idec, and Novartis.