Background/Purpose: Invariant Natural Killer T cells (iNKT) express an invariant T cell receptor (TCR) alpha chain and recognize lipid antigens – such as alpha-GalCer (aGC), presented by CD1d. iNKT cells differentiate in the thymus into one of three distinct populations: iNKT1, iNKT2 and iNKT17, which are analogous to Th1, Th2 and Th17. In arthritis iNKT cells have been found to either promote or suppress disease, an effect that could be attributed to involvement of distinct populations of iNKT cells. However, the differentiation and function of iNKT subsets during arthritis have not been explored. We use the Zap70-mutant BALB/c SKG mouse, which develops autoimmune arthritis due to defective thymic selection of CD4 T cells, to explore iNKT cell subsets during arthritis development.

Methods: Arthritis induced by mannan injection was evaluated in NKT deficient (CD1d^-/-) and NKT sufficient (CD1d^+/-) SKG mice. Also, iNKT cells were depleted in SKG mice by injection of an NKT cell-depleting antibody two days before arthritis onset. CD4 SKG T cells were adoptively transferred into RAG2-KO mice, alone or in combination with thymic iNKT cells. aGC was injected once on the day of arthritis onset in WT and IFNy^-/- SKG mice. Flow cytometry was used to evaluate iNKT cells in arthritic joints and the development of iNKT cells in the thymus of SKG and WT BALB/c mice.

Results: In SKG mice disease severity correlated with a reduced frequency of iNKT1 (r=-0.7914, P=0.0003) and an expansion of iNKT17 (r=0.7938, P=0.0003) in arthritic joints. Furthermore, in SKG mice deficient for iNKT cells, either following genetic deletion of CD1d or by antibody mediated depletion, severity of arthritis was exacerbated (P=0.009 and P=0.03 respectively). In line with these results, adoptive transfer of SKG iNKT cells ameliorated development of arthritis in RAG2-KO mice in co-transfer of CD4 SKG T cell (P=0.01). SKG mice showed an altered thymic development of iNKT subsets, with an increased frequency of iNKT1 (P<0.0001) and reduced frequencies of iNKT2 (P=0.0002) and iNKT17 (P=0.0016). Activation of iNKT cells in vivo using aGC ameliorated arthritis in SKG mice (P=0.05) through an IFNγ dependent mechanism.

Conclusion: We identify an immune regulatory mechanism by which arthritogenic abnormalities of CD4 T cell selection are associated with enhanced development of arthritis-protective iNKT1 and propose that activation of iNKT1 could be a beneficial therapeutic intervention in rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inkt-mediated-immunoregulatory-feedback-control-development-of-autoimmune-arthritis-in-mice/