A distinct human CD4+ T cell subset that secretes CXCL13 in rheumatoid synovitis.

Abstract

[Objective] ]Human CD4+ T cells in synovitis of rheumatoid arthritis (RA) produce CXCL13, a chemokine crucial for the formation of germinal center. This study was undertaken to determine the relevance of this population to known subsets of helper T cells and to proinflammatory cytokines and how these cells are generated. [Methods] The expression of Th markers and CXCL13 in CD4+ T cells of RA synovitis and the involvement of proinflammatory cytokines in CXCL13 production were assessed. We also investigated whether CXCL13+CD4+ T cells could be newly induced. [Results] CXCL13+CD4+ T cells of RA synovitis were negative for interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-17, Foxp3, and CXCR5, and expressed low levels of ICOS, indicating that this population is a distinct human CD4 subset. T cell receptor (TCR) stimulation of CD4+ T cells from RA synovitis with low expression of CXCL13, promptly induced CXCL13 production, and addition of proinflammatory cytokines supported the long-term production of CXCL13, indicating that CXCL13-producing CD4+ T cells can be in a memory state ready to be reactivated upon TCR stimulation, and that proinflammatory cytokines are involved in persistent CXCL13 production. TCR stimulation of blood CD4+ T cells from healthy volunteers together with proinflammatory cytokines induced a population that produced CXCL13 but not IFN-γ. Synovial T cells recruited CXCR5+ cells in a CXCL13-dependent manner. [Conclusion] CXCL13-producing CD4+ T cells induced in RA synovitis may play a role in the recruitment of CXCR5+ cells, such as B cells and circulating Tfh cells, and in ectopic lymphoid neogenesis in inflammatory sites.