Pathogenic Role of MIF Receptor (CD74) Expressing T cells in Inflammatory Arthritis

High expression alleles of the innate cytokine, macrophage migration inhibitory factor (MIF), are associated with the development or the severity of autoimmune inflammatory diseases, including rheumatoid arthritis. Numerous studies support MIF's role in activating inflammatory pathways and MIF inhibition reduces joint pathology in different experimental models of arthritis. We examined the impact of gene deletion of MIF or its cognate receptor CD74 in the T cell-dependent model of collagen-induced arthritis (CIA) and observed the complete absence of arthritis development, suggesting an unforeseen role for MIF/CD74 signaling in the development of arthritogenic T cells. While MIF has been shown in model systems to contribute to T cell activation by augmenting innate responses, fewer than 1% of T lineage cells express CD74 in naïve spleens and lymph nodes, and its functional consequences in pathogenic T cell subpopulations have not been studied. We found CD74+ T cells to expand during CIA and to increase in number within joint synovium, where they express an effector memory phenotype and recapitulate CIA development upon transfer into naïve mice. We further found evidence for the presence of CD74+ T cells in the circulation and joint synovium of patients with rheumatoid arthritis. MIF-dependent, CD74+ T cells may contribute to the chronicity of rheumatoid synovitis and to disease relapse in previously inflamed joints. Overall design: Single cell suspensions were prepared from the 3 spleens of mice either naïve or 28 days after injection with CFA + Chicken Type II collagen. Samples were then barcoded using TotalSeq Ahashtags (BioLegend, San Diego, CA). The samples were processed at Yale's W.M. Keck Biotechnology Resource Laboratory with 10x Genomics (Pleasanton, CA) microfluidics for single cell isolation with RNA sequencing performed on the resulting plates.