Background/Purpose: Systemic lupus erythematosus (SLE) is a leading cause of death for young women, and over 75% of SLE patients experience skin manifestations – cutaneous LE (CLE). Mechanisms of CLE pathogenesis are still unknown, so treatments rely on broad immunosuppression. Mucosal-associated invariant T cells (MAITs) are innate-like T cells that respond to microbial-derived antigens and have tissue repair capacity but are decreased in SLE. Here, we present new findings supporting a protective role for MAITs in SLE/CLE.

Methods: SLE and healthy PBMCs were analyzed by spectral cytometry (Dartmouth) and CytOF (Brigham, 145 SLE, 40 healthy). In 12-24 week old female MRL/lpr mice, spontaneous skin lesions (score >10) or systemic SLE (proteinuria) were treated with topical or systemic MAIT antigen (5OPRU, 1mM). 8-week-old female B6 and MAIT-deficient (Mr1-/-) mice were treated with imiquimod (TLR7 agonist) to induce SLE-like skin disease. MAIT profiling and expansion in non-lesional skin were conducted in 8-week-old female mice: MRL/lpr, B6, and Mr1-/-. Immune responses were assessed by flow cytometry; MAITs were identified by 5OPRU-loaded MR1 tetramer.

Results: MAIT cells were reduced in the circulation of SLE patients and had an activated/exhausted phenotype (CD25hiCD38hiCD69hi and CD107loCXCR3loCCR5lo), compared to healthy MAITs. In SLE-like skin of MRL/lpr mice, MAIT cells were reduced and more activated (> %CD69+PD1+), compared to controls (B6, MpJ). Topical administration of MAIT antigen (5OPRU) completely and durably resolved active CLE-like skin lesions. In contrast, skin lesions in mice treated with vehicle or 5OPRU + anti-MR1 Ig (blocks MAIT interaction with 5OPRU) never healed and continued to flare after treatment cessation. In the TLR7 agonist model of SLE, MAIT-deficient skin (Mr1-/-) had significantly increased expression of inflammatory (Ifng, Gzmb, Csf1) and interferon-stimulated genes, compared to the skin of imiquimod-treated B6 mice. MAIT expansion with 5OPRU (~5-10-fold) in SLE-like non-lesional skin stimulated proliferation and expansion of regulatory T cell (Treg) and suppressed inflammatory and cytotoxic gene expression (Gzmb, Ifng, il6, Tnf). In SLE mice with marked proteinuria, systemic delivery of 5OPRU halted the rise in serum inflammatory cytokines (CXCL1, GCSF, IL2, IFNg) and stimulated systemic expansion of Treg, including in the skin. The 5OPRU-mediated Treg expansion was MAIT-dependent, as no increase in Treg was seen in 5OPRU-treated Mr1-/- mice. MAIT expansion was captured in the skin after just 2 doses of 5OPRU and was accompanied by increases in monocyte-derived dendritic cells (moDCs) and Langerhans cells (LCs), in a MAIT-dependent fashion.

Conclusion: Topical and systemic expansion of MAITs reduces tissue and systemic inflammation, and overall disease burden in MRL/lpr mice. Their protective role in SLE is further supported by a second SLE model, where MAIT deficiency leads to heightened inflammatory and interferon responses. These effects may be mediated via MAIT-dependent expansion of Treg. MoDCs and LCs are identified as candidate antigen-presenting cells involved in MAIT activation and downstream Treg induction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mait-cell-mediated-immune-modulation-in-lupus-antigen-driven-expansion-as-a-protective-strategy/