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Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis.

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). IFN? 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.

SUBMITTER: Liu R

PROVIDER: S-EPMC4531289 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis.

Liu Rui R Li Xia X Zhang Zhuoya Z Zhou Min M Sun Yue Y Su Dinglei D Feng Xuebing X Gao Xiang X Shi Songtao S Chen Wanjun W Sun Lingyun L

Scientific reports 20150811

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 cel ...[more]

PMID: 26259824

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Project description:Objective: Recent studies on follicular regulatory T (Tfr) and follicular helper T (Tfh) cells suggest that they may participate in the pathogenesis of rheumatoid arthritis (RA). Here, we examine Tfr-like and Tfh-like cells and their subsets in RA and assess the correlations between these subsets with B cells and cytokines related to the pathogenesis of RA and their clinical significance. Methods: The study population consisted of 18 healthy controls and 47 RA patients (17 new onset, 57.00 ± 11.73 years; 30 treated RA patients, 57.56 ± 1.97 years). Disease activity scores in 28 joints were calculated. The positive rates of rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) were 82.9 and 89.4%, respectively. Cell subsets were analyzed using flow cytometry, and serum cytokine levels were measured using cytometric bead array. Results: Tfh-like and PD-1+ Tfh-like cells were elevated, and the distribution of Tfh-like cell subsets was altered with increased Tfh17-like and Tfh1/17-like cells in RA patients. The receiver operating characteristics curves for Tfh-like, Tfh17-like, Tfh1/17-like, and PD-1+ Tfh-like cells indicate improved RA diagnostic potential. RA patients had decreased regulatory T (Treg), Tfr-like, and memory Tfr-like (mTfr-like) cells and increased Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and their subsets, including Tfh1-like, Tfh2-like, Tfh1/17-like, and PD-1+ Tfh-like cells, were positively correlated with B cells. Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios were positively correlated with B cells in new-onset RA. Interleukin (IL)-2, IL-4, IL-17, interferon-γ, and tumor necrosis factor-α were positively correlated with Tfr-like and mTfr-like cells. IL-2 and IL-10 were positively correlated with Tfh-like and Tfh2-like cells. IL-4 was positively correlated with Tfh-like cells. Conclusions: Tfh-like and PD-1+ Tfh-like cells are increased, whereas Treg, Tfr-like, and mTfr-like cells are decreased in RA, leading to an imbalance in Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios. Tfh-like cells and a portion of their subsets as well as Tfh-like/Treg, Tfh-like/Tfr-like, and Tfh-like/mTfr-like cell ratios are closely related to B cells. Dysfunction of cell subsets leads to abnormal levels of cytokines involved in the pathogenesis of RA. The altered distributions of Tfh-like cell subsets, especially Tfh1/17-like cells, represent potential therapeutic targets for treatment of RA.

Project description:IntroductionInterleukin (IL)-21 is a member of type I cytokine family. Recent studies indicate that IL-21 can promote T follicular helper (Tfh) cell differentiation and survival, a specialized T cell subset which provides help for B cell. It can also regulate the activation, proliferation and differentiation of human B cell and immunoglobulin (Ig) production as well as isotype switching of plasma cell. Rheumatoid arthritis (RA) is characterized by auto-antibodies overproduction such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, suggesting a pivotal role of Tfh cell and B cell in the pathogenesis of RA. This study aimed to investigate whether IL-21 had a regulatory effect on Tfh cell and B cell in RA.MethodsSerum IL-21 concentrations were measured by ELISA. The correlations between serum IL-21 levels and clinical features of RA patients were analyzed by Spearman's rank test. The percentages of Tfh-like cells, IL-21 receptor (R) expression on Tfh-like cells and B cells in peripheral blood (PB) were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) were stimulated by rIL-21 (100 ng/ml) in the presence or absence of anti-CD40 and/or anti-IgM, and changes of IL-21R, activation-associated surface markers (CD25, CD69 and CD40), the proliferation, apoptosis and differentiation of B cells were analyzed by flow cytometry. Production of IgG and IgM in the culture supernatants was determined by ELISA.ResultsThe results showed that the serum IL-21 levels in RA patients were significantly higher than that of healthy controls (HC). IL-21 concentrations were positively correlated with 28-joint count disease activity score (DAS28) and anti-CCP antibody in RA patients with high IL-21 levels. Furthermore, the frequencies of peripheral CXCR5+PD-1+CD4+ Tfh-like cells markedly increased in RA patients and the percentages of Tfh-like cells were positively correlated with DAS28 and anti-CCP antibody levels. Moreover, elevated IL-21 levels were also correlated with the frequencies of Tfh-like cells. IL-21R expression on both Tfh-like cells and B cells were significantly enhanced in RA patients. In cultures vitro, exogenous IL-21 upregulated IL-21R expression and activation-associated surface markers on B cells and promoted more B cell proliferation in RA than in HC. This IL-21-mediated effect could be reversed by IL-21R-specific neutralizing antibody. Importantly, IL-21 promoted more differentiation of B cell into plasmablast and higher levels of IgG and IgM production in RA than in HC.ConclusionsIncreased serum IL-21 levels in RA patients correlate with DAS28, anti-CCP antibody and frequencies of Tfh-like cells. IL-21 supports B cell activation, proliferation and antibody secretion via IL-21R pathway. Thus, IL-21 may be involved in the pathogenesis of RA and antagonizing IL-21 could be a novel strategy for the therapy of RA.

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Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis.

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Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis.

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