Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis

Abstract

Summary 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 used mass cytometry to evaluate activated T cells in joint tissue from patients with rheumatoid arthritis (RA), a chronic immune-mediated arthritis that affects up to 1% of the population2. This approach revealed a strikingly expanded population of PD-1hi CXCR5- CD4+ T cells in RA synovium. These cells are not exhausted. Rather, multidimensional cytometry, transcriptomics, and functional assays define a population of PD-1hi CXCR5- ‘peripheral helper’ T (Tph) cells that express factors enabling B cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hi CXCR5+ T follicular helper (Tfh) cells, Tph cells induce plasma cell differentiation in vitro via IL-21 and SLAMF5-interactions3,4. However, global transcriptomics robustly separate Tph cells from Tfh cells, with altered expression of Bcl6 and Blimp-1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in Tph cells. Tph cells appear uniquely poised to promote B cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

Identification of enhanced IFN-γ signaling in polyarticular juvenile idiopathic arthritis with mass cytometry

“…The stratifying naive CD4 T cells and classical monocytes (i.e., subsets with increased p-STAT1 and/ or p-STAT3 in patients compared with controls) were heterogeneous with varying expression levels of different surface markers. This is reminiscent of recent work using mass cytometry that demonstrated that synovial T cell infiltrates in rheumatoid arthritis were highly heterogeneous and that characterization of the CD4 T cell diversity facilitated potential discrimination of pathogenic and nonpathogenic variants of known T cell subsets (37,38). Similarly, NK cell heterogeneity identified with mass cytometry was shown to contribute to West Nile virus susceptibility (39,40).…”

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

“…We have recently applied mass cytometry to evaluate the heterogeneity of CD4+ T cells that infiltrate RA synovium [69]. With this high-dimensional analysis, we identified a T ‘peripheral helper’ (T PH ) cell population that is markedly expanded in RA synovium, constituting ~25% of synovial CD4+ T cells.…”

Synovial cellular and molecular markers in rheumatoid arthritis

“…A recent report describes a novel CD4+ T cell subset that is distinct from T follicular helper cells and that appears to be the principal T cell subset that drives B cell to plasma cell differentiation in RA synovium[98]. These cells express PD-1 and lack CXCR5, but express other chemokine receptors that direct migration to the joint.…”

“…These cells express PD-1 and lack CXCR5, but express other chemokine receptors that direct migration to the joint. Expression of surface SLAMF5 and secretion of IL-21 are important in the interaction of these cells with B lymphocytes[98]. Another group recently demonstrated that a subset of CD4+ IL-21-producing T cells was expanded in RA synovial fluid, and that some of these cells also produced TNF-α and RANK-ligand[99].…”