CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation1. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population2. This approach revealed a markedly expanded population of PD-1hiCXCR5−CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5− ‘peripheral helper’ T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
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This work was supported by T32 AR007530-31 and the William Docken Inflammatory Autoimmune Disease Fund (to M.B.B.), Mallinckrodt Research Fellowship (to D.A.R.), R01 AR064850-03 (to Y.C.L.), NIH 5U01GM092691-05, 1U19 AI111224-01 and Doris Duke Charitable Foundation Grant #2013097 (to S.R.), Rheumatology Research Foundation Scientist Development Award (to L.A.H.), K01 AR066063 (to L.T.D.), Arthritis Research UK programme grant #19791 (to C.D.B.), and Arthritis Research UK Clinician Scientist Fellowship #18547 (to A.F.). J.L.M was supported by the FP7-HEALTH-F2-2012-305549 EuroTEAM. P.A.N. was supported by P30 AR070253 and the Fundación Bechara. We thank A. Chicoine and the BWH Human Immunology Center Flow Cytometry Core for assistance with cell sorting.
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Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome
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