BackgroundRheumatoid arthritis (RA) is a prototypical autoantibody-driven autoimmune disease in which T-B interactions play a critical role. Recent comprehensive analysis suggests that PD-1+CD8+ T cells as well as two distinct IL-21-producing PD-1+CD4+ T cell subsets, follicular helper T (Tfh) and peripheral helper T (Tph) cells, are involved in the pathogenesis of RA. Herein, we aimed to clarify a generation mechanism of IL-21-producing CD8+ T cells in humans, and to characterize this novel subset in patients with RA.MethodsCD8+ T cells in the peripheral blood (PB) and synovial fluid (SF) of healthy control (HC) and patients with RA were subject to the analysis of IL-21 mRNA and protein. We evaluated the surface marker, cytokine and transcription profiles of IL-21-producing CD8+ T cells in HCPB, RAPB and RASF.ResultsIL-21-producing CD8+ T cells were enriched in the CD45RA-(memory) PD-1+, especially PD-1hi subpopulation, and IL-12 and IL-21 synergistically induced IL-21 production by naïve CD8+ T cells. Memory PD-1hiCD8+ T cells in HCPB facilitated plasmablast differentiation and IgG production in an IL-21-dependent manner. In addition, PD-1hiCD8+ T cells in RASF and RAPB produced large amounts of IL-21 and were characterized by high levels of CD28, ICOS, CD69, HLA-DR, and CCR2 but not CXCR5. Furthermore, PD-1hiCD8+ T cells expressed high levels of transcripts of MAF and PRDM1, a feature observed in Tph cells.ConclusionsIdentification of IL-21-producing PD-1hiCD8+ T cells expands our knowledge of T cell subsets with B helper functions in RA. Selective targeting of these subsets could pave an avenue for the development of novel treatment strategies for this disease.

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Accumulation of age-associated B cells (ABCs) with autoreactive properties contributes to the pathogenesis of autoimmune diseases. However, the mechanisms whereby ABCs are generated and maintained are not understood. Here, we show that continuous stimulation of the B-cell receptor (BCR) with self-antigens plays a crucial role in ABC generation from anergic B cells and that this signal is vital for sustaining ABCs during aging and autoimmunity. In ABCs, BCR signaling was constitutively activated, and the surface BCR was internalized in vivo, as occurs in autoreactive B cells chronically exposed to self-antigens. With aging, ABCs were generated from autoreactive anergic B cells, but not from B cells expressing non-self-reactive BCR. In vitro stimulation of anergic B cells with self-antigen, interleukin-21, and Toll-like receptor 7/9 agonists promoted their differentiation to ABCs. Furthermore, the cellular phenotype of ABCs in Bm12-induced lupus mice resembled that of ABCs in aged mice, showing activation of BCR signaling, expression of activation markers, and BCR internalization. Importantly, Btk was persistently activated in ABCs of aged/autoimmune mice and humans with lupus. Pharmacological Btk inhibition resulted in a marked reduction in the number of ABCs and pathogenicity in lupus mice. Our findings have implications for accumulating ABCs and developing therapies for autoimmune diseases.