Adoptive transfer of a novel MIF receptor (CD74+) expressing memory T cell subpopulation is sufficient to transfer inflammatory arthritis

Abstract

Abstract Rheumatoid arthritis (RA) is characterized by relapsing disease and progressive autoimmune joint destruction. The mechanism(s) for disease recurrence in previously affected joints is unknown. High expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe erosive RA. We report a novel subpopulation of T cells expressing the MIF receptor CD74, which previously has not been considered to be present in T lineage cells. CD74+ T cells comprise 1% of lymph node T cell and exhibit an effector memory phenotype (CD3+ CD74+ CD44+, CD62Llow). Notably, whole genome expression profiling (RNAseq) of CD74+ T cells revealed reduced expression of the immune checkpoint Ctla4 (3.5-fold, p=0.009), and increased expression of Stat4 and Ptpn22 (1.4-fold, p=0.001 and 0.86-fold, p=0.045), three genes that regulate T cell activation and also are linked genetically to RA pathogenesis. In the collagen-induced arthritis (CIA) mouse model of RA, we observed a 2-fold (p=0.023) expansion of CD74+ T cells after disease induction when compared to Mif−/− mice, which show no expansion of CD74+ T cells and reduced disease severity (disease score: WT: 7.8; Mif −/−: 1.4, p>0.001). Notably, adoptive transfer of CD74+ T cells from mice with established CIA into naive mice recapitulated joint inflammation (disease score: 4.3, p=0.001). Disease was not detectable in naïve mice that received CD74-T cells from CIA hosts. This study identifies a novel population of effector memory T cells that are capable of transferring autoimmune joint inflammation. We hypothesize that MIF responsive CD74+ effector memory T cells mediate recurrent joint inflammation and may be amenable to specific targeting by emerging MIF-directed therapies.