Abstract
T follicular helper (Tfh) cells provide help for antigen-specific B cells. We have previously shown that Tfh cell frequency was increased and associated with auto-antibodies in patients with rheumatoid arthritis (RA), suggesting a possible involvement of Tfh cells in its pathogenesis. Mesenchymal stem cells (MSCs) represent a promising alternative cell therapy for RA by modulating T and B cell activation and proliferation. However, it remains unknown whether MSCs have immunoregulation on Tfh cells. In this paper, we have demonstrated that allogeneic MSCs could suppress Tfh cell differentiation in RA patients partly via the production of indoleamine 2,3-dioxygenase (IDO). IFNγ generated from Tfh cell differentiation system induced IDO expression on MSCs. MSCs transplantation (MSCT) into collagen-induced arthritis (CIA) mice prevented arthritis progression by inhibiting both the number and function of Tfh cells in vivo. These findings reveal a novel suppressive function of MSCs in Tfh cells, which has implication in understanding the underlying mechanisms of the immunotherapeutic effects of MSCs on RA patients.
Highlights
Rheumatoid arthritis (RA) is characterized by persistent synovitis and systemic inflammation, frequently leading to cartilage and bone destruction
Umbilical cord (UC)-Mesenchymal stem cells (MSCs) did not inhibit the generation of CD4+CXCR5−T cells, and upregulated them both in RA and healthy control (HC) peripheral blood mononuclear cells (PBMCs) (Supplementary Fig. 3), suggesting that CD4+CXCR5+T cells not CD4+CXCR5−T cells might be susceptible to UC-MSCs-mediated suppression
We found that the frequency of CD4+CXCR5+PD-1+T cells was substantially reduced, along with lower supernatant IL-21 levels in the presence of UC-MSCs (Fig. 1a,b), suggesting that UC-MSCs inhibited T follicular helper (Tfh) cell differentiation
Summary
Rheumatoid arthritis (RA) is characterized by persistent synovitis and systemic inflammation, frequently leading to cartilage and bone destruction. Auto-antibodies to citrullinated cyclic peptides (CCP) and rheumatoid factor (RF) have been indicated to be associated with this disease course[8,9,10]. We have previously demonstrated that the frequency of circulating Tfh cells was substantially upregulated in RA patients and positively correlated with 28-joint count disease activity score (DAS28) and serum anti-CCP antibody level, suggesting that Tfh cells might be involved in the pathogenesis of RA11. MSCs represent a promising cell therapy for autoimmune diseases including experimental and clinical RA16,17, systemic lupus erythematosus (SLE)[18,19,20,21], systemic sclerosis (SSc)[22], and Sjögren’s syndrome (SS)[23]. We have previously shown that refractory RA patients achieved a reduction of erythrocyte sedimentation rate (ESR), DAS28 and pain visual analog scale (VAS) score after allogeneic MSCs transplantation[24]. How allogeneic MSCs exert their immunoregulation in RA remains unclear
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