Human PD-1hiCD8+ T Cells Are a Cellular Source of IL-21 in Rheumatoid Arthritis

Abstract

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.

CD20+T cells are associated with inflammatory responses in experimental arthritis

“…We have shown that the CD4 + CD20 + T cell population is enriched with TFH and TPH; CD8 + CD20 + T cells also harbor subsets with similar features to TFH and TPH. In agreement with suggestions in RA (66), our data suggest that CXCR5 + PD-1 + CD8 + T cells CXCR5 -PD-1 + CD8 + T cells in concert with TFH and TPH play an essential role in augmenting pathology in CIA. The capacity of CD4 + CD20 + T cells to induce the expansion of cognate B cells and the production of class-switched antibodies warrants investigation.…”

“…A recent report showed that PD-1 + CD8 + T cells also produce increased amounts of IL-21 that allow B cell differentiation; these cells were abundant in RA patients' peripheral blood and synovial fluid. Of note, the PD-1 + CD8 + T cell subset expressed CCR2 but not CXCR5 (66).…”

Identification of Diagnostic Signatures and Immune Cell Infiltration Characteristics in Rheumatoid Arthritis by Integrating Bioinformatic Analysis and Machine-Learning Strategies

“…The degree of macrophage infiltration in joint tissues and the level of monocytederived cytokines in serum show positive correlations to disease severity (7). CD8+ T cell exhibits anti-inflammation characteristic and is likely to contribute to the reduction of persistent autoimmune responses in rheumatoid joints (8,9). B cells impact bone remodeling in RA (10).…”

Adaptive immunity in the joint of rheumatoid arthritis

“…Notably, CD8 T cells of any subsets express higher levels of IFN-c than any CD4 T cells in RA joint. Regarding PD-1þ CD8 T cells in RA joint, we recently found them producing IL-21 and not expressing CXCR5, similar to Tph cells [90]. An association between ELN formation in the synovium and the presence of CD8 T cells expressing CD40L was also shown [91].…”