Background/Purpose: Most systemic lupus erythematosus (SLE) patients experience sensitivity to ultraviolet (UV) light, which can trigger disfiguring skin lesions or systemic flares. In healthy skin, UV light promotes a robust immunosuppressive response, driven in part by the expansion of regulatory T cells (Treg). In contrast, UV light instead elicits an inflammatory response in SLE skin. The cellular mediators that drive Treg response in healthy skin and the mechanisms by which this response fails in SLE remain incompletely understood. Here, we present new findings that implicate mucosal-associated invariant T cells (MAITs) in the (dys)regulation of skin response to UV light in healthy and lupus skin.

Methods: 8-week-old female B6, MAIT-deficient (Mr1-/-), and SLE (MRL/lpr or imiquimod, TLR7/8 agonist) mice were exposed to chronic low-dose UVB (50mJ/cm2 daily, 2 or 6 doses). Skin MAITs were expanded by topical application of MAIT antigen, 5-OP-RU (1mM, every 48hr x 4). Skin inflammatory responses, including MAIT detection by 5-OP-RU-loaded MR1 tetramer, were quantified by scRNAseq and flow cytometry.

Results: In healthy (B6) skin, UV light stimulated ~5-fold expansion of both MAIT cells and Treg. MAITs were required for UV-induced Treg expansion, as no increase in skin Treg proportion or number was seen in MAIT-deficient (Mr1-/-) mice following UVB. Moreover, Treg in MAIT-deficient skin did not proliferate (no change in %Ki67+ vs. >10% increase in Ki67+ in B6 skin) and exhibited a fragile phenotype early after UVB (only 2 doses): Neuropilin-1lowGITRlowICOSlow but PD1highCD69high. Consistent with a potential tolerogenic role of myeloid cells in the skin, Langerhans cells (LCs), monocyte-derived dendritic cells (moDCs), and type 2 dendritic cells (cDC2s) expanded only in B6 but not Mr1-/- skin after two doses of UV light. Like in Mr1-/- skin, Treg did not proliferate or expand in response to UV in SLE-prone (MRL/lpr) skin, which is low in MAITs (~2% of TCRb+ T cells vs. ~12% in B6 skin). In the absence of Treg expansion, CD8+ T cells increased ~10-20-fold in MRL/lpr skin, leading to a marked reduction in the Treg:CD8 ratio. The same reduction in the Treg:CD8 ratio following UV was observed in the TLR7/8 model of SLE in Mr1-/- but not B6 skin. The CD8s that expanded in SLE-like skin expressed high Ki67, CD69, PD1, and CXCR6. Exposing SLE-like skin to UV after first topically expanding MAITs restored the Treg:CD8 ratio, and the CD8 T cells in MAIT-expanded UV-exposed skin expressed lower levels of Ki67, CD69, PD1, and CXCR6, compared to UV-exposed skin without prior MAIT expansion.

Conclusion: In healthy skin, UV-induced proliferation and immunosuppressive phenotype of Treg are dependent on MAIT cells and may require the contribution of a subset of myeloid cells, such as LCs, moDCs, or cDC2s. SLE-like skin fails to mount the Treg response to UV light, which enables proliferation and activation of CD8 T cells, known contributors to SLE skin pathology. The failure of the UV-induced MAIT-Treg axis in SLE skin can be reversed by topically expanding MAIT cells prior to UV exposure, revealing a novel therapeutic strategy to mitigate photosensitive skin reactions in lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treg-need-a-mait-investigating-the-contribution-of-mait-cells-to-impaired-uv-induced-treg-expansion-in-lupus-photosensitive-reactions/