Antigen-driven MAIT cell activation restores skin Treg levels and attenuates lupus-like skin inflammation 2257534

Abstract

Abstract Introduction MAIT cells are innate-like T cells with both repair and inflammatory capacity. Their role in inflammatory skin disease is unknown. Here, we report a protective role for MAIT cells in lupus skin disease. Methods Lupus and healthy PBMCs were analyzed by spectral cytometry (Dartmouth) and CyTOF (Brigham, 145 SLE, 40 healthy). B6, MAIT-deficient (Mr1-/-), and SLE (MRL/lpr or TLR7 agonist) mice (8-24wks, F) received topical or systemic MAIT antigen (5OPRU, 1mM). MAITs (5OPRU-loaded MR1 tetramer) and Treg were assessed by flow cytometry. ScRNA-seq of MAITs and Treg was conducted using 10X Genomics. Results MAITs are reduced and activated in circulation of SLE patients, compared to healthy donors. In MRL/lpr (MRL) skin, MAITs are reduced ∼10-fold compared to controls (B6, MpJ) and are CD69+PD1+. Topical antigen 5OPRU, but not vehicle or 5OPRU + anti-MR1 IgG (prevents MAIT-MR1 interaction) resolved severe skin lesions. MAIT expansion in non-lesional MRL skin stimulated Treg expansion and suppressed inflammatory and cytotoxic genes (Gzmb, Ifng, Il6, Tnf). In MRL mice with proteinuria, systemic 5OPRU prevented increases in serum inflammatory cytokines (CXCL1, GCSF, IL2, IFNg) and drove systemic expansion of Treg, including in skin. In the TLR7 SLE model, inflammatory (Ifng, Gzmb, Csf1) and interferon-stimulated (Ifi27l2ra, Isg20) genes were increased in Mr1-/- compared to B6 skin. Topical 5OPRU increased Treg:CD8 ratio in B6 but not Mr1-/- skin. ScRNA-seq of 5OPRU-treated skin MAITs revealed a tissue repair transcriptional profile (Furin, Tgfb1, Lgals3). 5OPRU-driven Treg expansion was MAIT-dependent (no expansion in Mr1-/- skin) and heterogeneous, revealing equal expansion of 7 distinct Treg subsets in B6 skin. Conclusion Antigen-driven MAIT activation supports Treg expansion and reduces morbidity in MRL/lpr mice. Conversely, MAIT deficiency heightens inflammation in a second SLE model, further supporting a protective role for MAITs in inflammatory skin disease, likely through a novel MAIT-Treg axis. Funding Source NIAMS R01AR080641 LFA Gina M. Finzi Memorial Fellowship Topic Categories Basic Autoimmunity (BA)