Aberrant pro-inflammatory responses of CD20+ T cells in experimental arthritis

Autoimmune conditions such as rheumatoid arthritis (RA) are characterized by lymphocytic tissue infiltrates containing aberrant T and B cells and innate immune cell populations critical in disease pathogenesis [1]. Various subtypes of T cells, including Th1 and Th17, participate in immune-mediated inflammation of RA, where they become activated and accumulate in the inflamed joints [1], [2]. These T cells produce pro-inflammatory cytokines [3], [4] and help B cells proliferate and secrete essential proteins such as rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPA). B cells, in turn, mediate T cell activation through the expression of costimulatory molecules [1].

CD20 is a 33-37 kDa non-glycosylated protein that belongs to the membrane-spanning 4-domain A (MS4A) protein family [5], it is found in the majority of B cells starting from late pre-B cells, and its expression is lost in terminally differentiated plasmablasts and plasma cells [6], [7]. B cell depletion by targeting CD20 using anti-CD20 monoclonal antibodies (mAbs) such as rituximab (RTX) has proved beneficial in RA [8] and other autoimmune conditions, including multiple sclerosis (MS) [9]. The rationale for targeting anti-CD20 mAbs in RA was that removing autoantibody-producing or T cell-activating B cells would improve clinical outcomes in patients [10], [11]. However, although RTX reduces autoantibody titers, this effect does not explain its anti-inflammatory activity, which develops before the decrease in autoantibody titers is observed.

Multiple analyses have consistently demonstrated the expression of CD20 by a subset of CD3+ T cells [12], [13], [14], [15], [16], [17], [18]. CD3+CD20+ T cells were found in the peripheral blood of RA patients and other human autoimmune syndromes, such as MS, Primary Sjogren’s syndrome, and Psoriasis [13], [14], [15], [17], [18]. This CD20 expressing T cell subset exhibited pro-inflammatory features such as IFNγ, IL-1β, IL-17, IL-2, IL-8, transforming growth factor β (TGF-β) and TNFα, and C-C chemokine receptor type 2 (CCR2), CCR5, CCR6; these cytokines and chemokine receptors play crucial roles in homeostasis as well as pathologic immune contribution in various diseases, including RA [13], [14], [15]. Like CD20+ B cells, CD3+CD20+ T cells were eliminated with RTX treatment [9], [13], [15], [16], [17]. Hence, the therapeutic effect of anti-CD20 mAbs has also been attributed to the depletion of this highly inflammatory CD20+ T cell subset [17].

Animal models of RA have provided insights into basic pathogenic mechanisms of chronic inflammatory arthritis and autoimmune disease in general. Collagen-Induced Arthritis (CIA) is a well-established experimental RA model to study pathogenesis and its underlying immunological basis. It shares several critical characteristics of the disease pathogenesis with RA, including CD4+ T cell-mediated inflammation and extensive cartilage and bone damage, resulting in joint deformities [19]. Susceptibility to CIA is related to the murine MHC class II molecule H-2q whose peptide-binding pocket has a similar primary structure to the shared epitope of RA-associated HLA-DR molecules [20].

The prevalence and contribution of CD20+ T cells in RA have primarily been examined in the peripheral blood; however, the inflammatory role of these cells at the site of inflammation is unclear. This study used the CIA model to investigate the phenotype and functional relevance of CD20-expressing T cells in the lymph nodes and arthritic joints of CIA mice using multicolour flow cytometry and immunohistochemistry techniques. We report draining lymph nodes, and inflamed tissue of DBA1/J mice harbour CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells. These cell populations are expanded in mice undergoing CIA, and they display a pro-inflammatory phenotype and exhibit features associated with promoting inflammatory B cell responses. Our findings are suggestive that CD20+ T cells might contribute to pro-inflammatory processes in CIA.

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