Background/Purpose: Mucosal-associated invariant T (MAIT) cells are innate T cells that are restricted by the nonpolymorphic MHC-related molecule-1 (MR1) and express a semi-invariant TCRα chain: Vα7.2-Jα33 in humans and Vα19-Jα33 in mice. Previously, we reported that the activated status of MAIT cells correlated with disease activity in patients with systemic lupus erythematosus (SLE), and MAIT cells were accumulated in the kidneys from patients with lupus nephritis. Because MAIT cell deficiency reduced autoantibody production and the disease severity in FcγRIIb^-/-Yaa mice, a spontaneous animal model of lupus, we investigated mechanisms by which MAIT cells enhanced autoimmune response and investigated whether MAIT cells could be therapeutically targeted in lupus.

Methods: FcγRIIb^-/-Yaa mice were crossed to MR1-deficient mice lacking MAIT cells, and the levels of serum anti-dsDNA antibody and urinary albumin were measured. The severity of nephritis was assessed histologically. T and B cell subsets in the spleen and kidneys at 2 months of age were analyzed by using flow cytometry. To evaluate whether inhibition of MAIT cell activation suppress the disease course of lupus, FcγRIIb^-/- Yaa mice were treated with isobutyryl 6-formyl pterin (i6-FP), a suppressive MR1 ligand, orally three times weekly for 4 weeks starting at 4 weeks of age. B cells from FcγRIIb^-/-Yaa mice were stimulated with lipopolysaccharide in the presence of MAIT cells and autoantibody production was assessed by ELISA.

Results: Activated MAIT cells were infiltrated into the kidneys of FcγRIIb^-/-Yaa mice. Reduced autoantibody production and disease severity by MR1 deficiency was associated with reduced germinal center and T cell responses in FcγRIIb^-/-Yaa mice. The suppression of MAIT cell activation by i6-FP administration decreased serum anti-dsDNA antibody levels and the deposition of IgG and C3 in the glomeruli. i6-FP administration also reduced germinal center responses and activated T cell infiltration into kidneys in FcγRIIb^-/-Yaa mice. MAIT cells directly enhanced autoantibody production by B cells in vitro, and this was markedly reduced by blocking CD40L-CD40 or the MR1-TCR pathway.

Conclusion: MAIT cells exacerbated the disease severity of lupus by enhancing autoantibody production and tissue inflammation in FcγRIIb^-/- Yaa mice. MAIT cells enhanced autoantibody production by B cells dependent on the CD40-CD40L and TCR pathways. Together with our previous findings in patients with SLE, MAIT cells may contribute to lupus pathology and serve as potential novel therapeutic target for autoimmune diseases such as SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mucosal-associated-invariant-t-cells-can-be-therapeutically-targeted-in-lupus/