Newly Identified T Peripheral Helper (Tph) Cells in Rheumatoid Arthritis

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Rheumatoid arthritis (RA) is a prototypical autoimmune disease characterized by activation of autoreactive T cells and B cells, production of autoantibodies, and accumulation of lymphocyte aggregates within the synovium. Recently, we described a population PD-1hi CD4+ T cells that we called T `peripheral helper' (Tph) cells that is markedly expanded within RA synovium and possesses the capacity to infiltrate inflamed tissues and promote B cell maturation and antibody production (Rao et al., Nature, 2017). Tph cells share several features with T follicular helper (Tfh) cells, the principal T cell subset known to drive B cell maturation in secondary lymphoid tissues. Like Tfh cells, synovial Tph cells express high levels of IL-21, which promotes B cell survival, and CXCL13, a B cell chemoattractant. Yet, Tph cells differ from Tfh cells in expression of chemokine receptors for homing to inflammatory sites and in transcriptional regulators. The discovery of Tph cells has clinical implications for diseases that involve autoantibody production within tissues, including RA and SLE. Selective targeting of Tph cells could potentially interrupt local production of autoantibodies and downstream inflammatory cascades. However, such targeting will require a precise characterization of the phenotype of pathologic Tph cells and a more complete understanding of the factors that drive Tph cell differentiation and expansion. Our current knowledge of Tph cells is limited. We propose in Aim 1 to define the heterogeneity and subpopulations of Tph cells using unbiased single cell transcriptomics followed by isolation of distinct subpopulations for functional analysis including cytokine production. In Aim 2, we gain insight into how cytokine signaling may alter Tph cells in vivo by tracking changes in Tph cell numbers and function in response to currently used targeted therapies for RA. Finally, in Aim 3 we determine what drives Tph cell differentiation and maturation. Together, these studies will advance our knowledge of the nature of newly identified Tph cells in RA and provide information critical to understanding their role in the immunopathogenesis of RA and potential applications for therapy.