Background/Purpose: Many systemic autoimmune rheumatic diseases, including systemic lupus erythematosus (SLE), Sjögren’s syndrome, and systemic sclerosis are highly female-biased. Although these diseases are more prevalent in females, disease severity is often greater in affected males. Transcriptional profiling of tissues from patients with these diseases has consistently revealed a prominent Type 1/2 interferon (IFN)-stimulated gene signature (ISG). The mechanisms by which sex modulates IFN-associated inflammatory responses in autoimmunity is unclear. The X chromosome contains several genes with roles in immune functions and IFN signaling, and our lab has shown that females with SLE exhibit impaired maintenance of X-chromosome inactivation (XCI) in circulating B and T cells. We therefore sought to determine how perturbed XCI maintenance in T cells modulates susceptibility to an inducible model of systemic autoimmunity using a toll-like receptor 7 (TLR7)-driven model associated with a strong ISG signature.

Methods: Female wild-type C57BL/6, CD4cre⁺Xist^+/+ (n= 12; “WT”), and CD4cre⁺Xist^fl/fl (n=4; “Xist CKO”) mice were treated topically with Imiquimod cream (IMQ; a TLR7 agonist; n=9) or Cetaphil lotion (VEH; n=7), thrice weekly for 10 weeks. Serum, spleen, kidney, and lung tissue were harvested upon euthanasia and processed for autoantibody quantitation, flow cytometry, and histology.

Results: Chronic IMQ treatment resulted in marked splenomegaly, T-cell activation, autoantibody production, and dermal, pulmonary, and renal inflammation. IMQ-treated Xist CKO mice tended to exhibit less splenomegaly and autoantibody production, fewer activated CD4⁺ and CD8⁺ T cells, and more Foxp3⁺ (X-linked) regulatory T cells (Tregs) compared to their WT counterparts. Xist CKO mice also tended to exhibit a greater proportion of Tregs expressing Cxcr3, an X-linked chemokine receptor integral for chemotaxis to sites of Type 2 interferon-mediated inflammation that has been shown to variably escape XCI.

Conclusion: These initial data suggest that impaired XCI maintenance in T cells may modulate Type 1/2 interferon-associated inflammation through an expansion of Foxp3⁺ Tregs, resulting in a less severe phenotype in this TLR7-driven model. Though further validation of these findings in larger experimental cohorts is required, our studies could provide new insights into factors influencing disease severity in female-biased autoimmune diseases associated with strong ISG signatures.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/impaired-x-chromosome-inactivation-maintenance-in-t-cells-is-associated-with-features-of-reduced-disease-severity-in-a-toll-like-receptor-7-driven-model-of-systemic-autoimmunity/