Background/Purpose:

A plethora of evidence from genome-wide association studies and relevant animal models implicates a pivotal role of T cells in the pathogenesis of rheumatoid arthritis (RA). CD8+ T cells comprise ~40% of all T cells infiltrating the rheumatoid synovium, and the number of activated CD8+ T cells in synovial fluids (SF) and peripheral blood (PB) of RA is associated with disease activity. Production of cytotoxic molecules such as granzyme B and perforin in CD8+ T cells is more pronounced in patients with RA than in healthy controls (HC).

Apart from their cytotoxicity, CD8+ T cells have recently gained attention as an IL-21-producing cell population. In mice a novel subset of IL-21-producing CD8+ T cells, like follicular helper CD4+ T cells (Tfh), is induced by IL-6 from naïve CD8+ T cells and capable of supporting B cell differentiation into Ab-producing cells. However, little is known about a role of human IL-21-producing CD8+ T cells, particularly in autoimmune diseases. Here, we have investigated a generation mechanism of IL-21-producing CD8+ T cells in humans, and also determined a role of this novel subset in patients with RA.

Methods:

CD8+ T cells in PB and SF from HC and patients with RA with or without CD3/28 stimulation were subject to the analysis of IL-21 expression at both mRNA and protein levels. To clarify a generation mechanism of IL-21-producing CD8+ T cells in humans, naïve (CD45RA+CCR7+) CD8+ T cells were highly purified using a flow cytometry and tested for their differentiation into IL-21-producing CD8+ T cells in the presence of multiple combination of cytokines along with CD3/28 stimulation. Moreover, using a flow cytometry we thoroughly analyzed the phenotype of a IL-21-producing CD8+ T cell subset in HCPB and RAPB as well as RASF. To determine whether IL-21-producing CD8+ T cells exert B-cell-helper functions, these cells were co-cultured with memory B cells.

Results:

CD3/28 stimulation induced IL-21 production in whole CD8+ T cells from HC, and central memory (CD45RA-CCR7+), but not naïve and terminal effector, CD8+ T cells were a main producer of IL-21. Among several cytokines extrapolated from studies of CD4+ T cell subsets,

IL-12 was the most potent cytokine to generate IL-21-producing CD8+ T cells from naïve CD8+ T cells. IFN-γ, IL-6 and IL-21 were also able to do so, albeit to a lesser extent. The surface phenotype of IL-21-producing CD8+ T cells was CD28+CD69+CD95+PD-1+, and these cells also had potential to produce IFN-γ, but not IL-17. Central memory CD8+ T cells stimulated with CD3/28 facilitated the differentiation from memory B cells (CD27+CD38-) to plasmablasts (CD27highCD38high) via up-regulation of expression of blimp-1 transcription factors. Compared with HCPB, central memory CD8+ T cells were pronounced in RAPB, and this trend was further prominent in RASF. Moreover, RASF enriched CD69+, CD95+ and PD-1+ CD8 + T cells than PB from HC and RA. Central memory CD8+ T cells in PB and SF from RA most significantly produced IL-21 among CD8+ T cell subsets.

Conclusion: Together, these findings suggest that IL-21-producing central memory CD8+ T cells are a novel subset that plays a pivotal role in the pathogenesis of RA by exerting B-cell-helper functions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-b-cell-helper-il-21-producing-cd8-t-cell-subset-involved-in-the-pathogenesis-of-rheumatoid-arthritis/