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 MAIT cells are activated in patients with systemic lupus erythematosus (SLE) and that the activation state of these cells correlated with disease activity. By using MR1 deficient mice lacking MAIT cells, we revealed that MAIT cells contribute to the disease severity of lupus in FcγRIIB^-/- Yaa mice. In this study, we asked how MAIT cells are involved in the pathogenesis in this lupus model and explored their potential as a therapeutic target for lupus. We also investigated whether MAIT cells infiltrate in the nephritic kidneys of lupus patients.

Methods:

FcγRIIB^-/- Yaa mice were crossed to MR1 deficient mice lacking MAIT cells, and disease progression was compared between MR1^-/- and MR1^+/+ FcγRIIB^-/- Yaa mice. 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. FcγRIIb^-/- Yaa mice were treated with a suppressive MR1 ligand(MR1L) orally three times weekly for 4 weeks starting at 4 weeks of age. Infiltration of MAIT cells was assessed in kidney biopsy specimens from lupus patients using a confocal microscope.

Results:

MAIT cell deficiency improved the disease course of lupus in FcγRIIb^-/- Yaa mice as shown by the increased survival rate, reduced serum anti-dsDNA antibody levels, glomerulonephritis scores and IgG and C3 deposition in glomeruli in MR1^-/- FcγRIIB^-/- Yaa mice. MAIT cells enhanced germinal center reaction which was accompanied by the increase of T follicular helper cells, germinal center B and plasma cells and the reduction of T regulatory and T follicular regulatory cells. The presence of MAIT cells enhanced cytokine producing capacity of T and innate-T cells in the spleen and kidneys. Activated MAIT cells were accumulated in the kidneys and produced inflammatory cytokines. Administration of MR1L decreased serum anti-ds DNA antibody levels and reduced germinal center B and plasma cells. The deposition of IgG and C3 in the glomeruli was also reduce in FcγRIIb^-/- Yaa mice treated with MR1L. MAIT cells were accumulated in the nephritic kidneys of lupus patients.

Conclusion:

MAIT cells exacerbated the disease severity of lupus by enhancing autoantibody production and tissue inflammation in FcγRIIb^-/- Yaa mice. MAIT cells were found in the nephritic kidneys of lupus patients, suggesting these cells may also contribute to lupus pathogenesis in human patients. As administration of MR1L suppressed the disease course of lupus, MAIT cells hold potential as a new therapeutic target for SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mucosal-associated-invariant-t-mait-cells-as-a-potential-therapeutic-target-for-systemic-lupus-erythematosus/