Dataset Information

T-Cell Immune Imbalance in Rheumatoid Arthritis Is Associated with Alterations in NK Cells and NK-Like T Cells Expressing CD38.

ABSTRACT:

Background

CD38+ NK (CD3- CD16+ CD38+ CD56+) cells were increased in rheumatoid arthritis (RA), which suppressed Treg cell differentiation. This study explored how CD38+ NK cells regulated CD4+ T-cell differentiation into Treg cells in RA.

Methods

Proportions of CD38+ NK cells and their counterpart CD38+ NK-like T (CD3+ CD16+ CD38+ CD56+) cells were measured in RA and rats with collagen-induced arthritis (CIA). CD38+ NK cells and CD38+ NK-like T cells were cocultured with CD4+ T cells, respectively.

Results

A significantly increased proportion of CD38+ NK cells and a decreased proportion of CD38+ NK-like T cells were detected in RA and CIA blood and synovial fluids. When CD4+ T cells were cocultured with CD38+ NK cells, mammalian target of rapamycin (mTOR) signaling was activated, and Th1/Th2 and Th17/Treg ratios were increased. When CD38+ NK cells were pretreated with anti-CD38 antibody, Treg cell proportion was increased, and Th1/Th2 and Th17/Treg ratios were decreased. CD38+ NK-like T cells showed the opposite results. CD38+ NK cells and CD38+ NK-like-T cells activated differential gene expressions and pathways in CD4+ T cells and initiated Th1 and Th2 cell differentiation by differential gene nodes.

Conclusions

This study suggest that the high CD38+ NK cell proportion and low CD38+ NK-like T cell proportion in RA suppress Treg cell differentiation by stimulating mTOR signaling in CD4+ T cells, which consequentially disturbs the immune tolerance.

SUBMITTER: Wang H

PROVIDER: S-EPMC9082181 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

T-Cell Immune Imbalance in Rheumatoid Arthritis Is Associated with Alterations in NK Cells and NK-Like T Cells Expressing CD38.

Wang Hongxing H Fang Kehua K Yan Weining W Chang Xiaotian X

Journal of innate immunity 20210824 2

<h4>Background</h4>CD38+ NK (CD3- CD16+ CD38+ CD56+) cells were increased in rheumatoid arthritis (RA), which suppressed Treg cell differentiation. This study explored how CD38+ NK cells regulated CD4+ T-cell differentiation into Treg cells in RA.<h4>Methods</h4>Proportions of CD38+ NK cells and their counterpart CD38+ NK-like T (CD3+ CD16+ CD38+ CD56+) cells were measured in RA and rats with collagen-induced arthritis (CIA). CD38+ NK cells and CD38+ NK-like T cells were cocultured with CD4+ T c ...[more]

PMID: 34428762

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Project description:BackgroundCD38+ NK cells are overabundant in rheumatoid arthritis (RA). Cyanidin-3-O-glucoside (C3G) is an inhibitor of CD38. This study investigated the pathogenic role of CD38+ NK cells and the effect of C3G on RA.MethodsRats with bovine type II collagen-induced arthritis (CIA) were injected with C3G. RA synovial fibroblasts (RASFs) or mononuclear cells (MNCs) were cultured with C3G. MNCs were also cocultured with CD38+ NK cells following C3G pretreatment.ResultsC3G injection significantly alleviated CIA. C3G also significantly increased the level of interleukin (IL)-10 and the regulatory T (Treg) cell proportion, and it decreased the interleukin (IL)-6 and interferon (IFN)-γ levels and CD38+ NK cell proportion in rat peripheral blood and synovial fluid. Additionally, C3G significantly increased RASF apoptosis and decreased RASF proliferation and IL-6 production in the culture medium. Furthermore, C3G stimulated MNCs to increase IL-2 and IL-10 production and the Treg cell proportion, and it caused MNCs to decrease IL-6 and IFN-γ production and the CD38+ NK cell proportion. Although CD38+ NK cells significantly decreased the Treg cell proportion and IL-10 level in MNCs, CD38+ NK cells that had been pretreated with C3G increased the proportion of Treg cells and IL-10 levels and decreased the IL-6 and IFN-γ levels in the coculture. In CD38+ NK cells, C3G significantly increased Sirtuin 6 (Sirt6) expression and the tumor necrosis factor (TNF)-α level, and it decreased natural killer group 2D (NKG2D) expression and the IFN-γ level. However, when CD38+ NK cells were treated with Sirt6 siRNA, C3G did not change the NKG2D expression, the TNF-α level sharply decreased, and the IFN-γ level increased. When MNCs were cocultured with C3G-pretreated CD38+ NK cells in the presence of TNF-α and an anti-IFN-γ antibody, the IL-10+ Treg cell proportion significantly increased. When MNCs were cocultured with C3G-pretreated CD38+ NK cells in the presence of IFN-γ and an anti-TNF-α antibody, the IL-10+ Treg cell proportion sharply decreased. When CIA rats were injected with both C3G and the Sirt6 inhibitor OSS_128167, the rats exhibited joint inflammation and a low Treg cell proportion, but the CD38+ NK proportion was still low.ConclusionC3G has therapeutic effects on CIA and RA. C3G decreased the proportion of CD38+ cells, RASF proliferation, and proinflammatory cytokine secretion, and it increased the Treg cell proportion. C3G also elevated Sirt6 expression to suppress NKG2D expression, increase TNF-α secretion, and decrease IFN-γ secretion in CD38+ NK cells, which stimulates MNCs to differentiate into Treg cells. This study also demonstrates that the inhibition of Treg cell differentiation in MNCs by CD38+ NK cells is a potential cause of the immune imbalance in RA and CIA.

Project description:ObjectiveEmerging research suggests that rheumatoid arthritis (RA) is associated with intestinal dysbiosis. This prospective pilot study evaluates changes in intestinal microbial composition in patients with RA initiating treatment with either methotrexate (MTX) or a tumor necrosis factor inhibitor (TNFi).MethodsConsecutive patients, fulfilling the 2010 American College of Rheumatology/EULAR classification criteria for RA, who started treatment with either MTX or TNFi delivered a stool sample upon initiation of immunosuppression and 3 months later. A 16S ribosomal RNA gene-based validated microbiota test (GA-map Dysbiosis Index Score [DIS], Genetic Analysis, Oslo, Norway) was used to evaluate for the presence and degree of dysbiosis. Fecal levels of Prevotella copri (P. copri) were analyzed by custom-made quantitative polymerase chain reaction. Changes in microbial composition were analyzed in relation to changes in disease activity, as measured by the disease activity score based on 28-joint counts, using C-reactive protein.ResultsAt baseline, dysbiosis was present in 33 of 50 (66%) participants and more common in participants with more than 2 years of disease duration (P = 0.019). At the 3-month follow-up, 27 of 50 (54%) were good treatment responders and the DIS had improved in 14 of 50 (28%). Participants initiating TNFi more often exhibited improvement in the DIS compared with those initiating MTX (P = 0.031). P. copri was identified in 32 of 50 (64%) at baseline. An improvement in disease activity score based on 28-joint counts, using C-reactive protein was associated with a simultaneous decrease in P. copri abundance (rs = 0.30, P = 0.036).ConclusionThis study affirms that dysbiosis is a feature of RA. Although patients were not randomized to MTX or TNFi, the findings suggest that specific therapies may differentially modulate the gastrointestinal microbiota in RA. The association between P. copri and treatment response requires further study.

Project description:ObjectiveIn rheumatoid arthritis (RA), autoreactive B cells are pathogenic drivers and sources of anti-citrullinated protein antibodies (ACPAs) that are a diagnostic biomarker and predictor of worse long-term prognosis. Yet, the immunobiologic significance of persistent ACPA production at the cellular level is poorly understood. This study was undertaken to investigate the representation of ACPA-expressing switched-memory B cells in RA.MethodsIn a cross-sectional study of RA patients, we investigated the presence of continued defects in immune homeostasis as a function of disease activity. Using an enzyme-linked immunosorbent assay (ELISA) and a sensitive multiplex bead-based immunoassay, we characterized fine binding antibody specificities in sera, synovial fluid (SF), and B cell culture supernatants. In this manner, we determined the frequency and epitope reactivity patterns of ACPAs produced by SF B cells and switched-memory blood B cells and compared the latter to serum ACPA levels and disease activity scores.ResultsCultured B cells from SF were shown to spontaneously secrete ACPAs, while constitutive IgG autoantibody production by peripheral blood mononuclear cells (PBMCs) was substantially less frequent. After in vitro stimulation, PBMCs secreted IgG ACPA that was overwhelmingly from switched-memory B cells, across all patient groups treated with methotrexate and/or a tumor necrosis factor inhibitor. Intriguingly, the frequencies of ACPA-expressing switched-memory B cells significantly correlated with serum IgG anti-cyclic citrullinated peptide 3 (r = 0.57, P = 0.003). Moreover, treatment-induced clinical remission had little or no effect on the circulating burden of switched-memory ACPA-expressing B cells, in part explaining the continued dysregulation of humoral immunity.ConclusionOur findings rationalize why therapeutic cessation most often results in disease reactivation and clinical flare. Hence, a clinical disease activity score is not a reliable indicator of the resolution of pathologic recirculating B cell autoimmunity.

Project description:BackgroundDozens of transplants generated from pluripotent stem cells are currently in clinical trials. The creation of patient-specific iPSCs makes personalized therapy possible due to their main advantage of immunotolerance. However, some reports have claimed recently that aberrant gene expression followed by proteome alterations and neoantigen formation can result in iPSCs recognition by autologous T-cells. Meanwhile, the possibility of NK-cell activation has not been previously considered. This study focused on the comparison of autologous and allogeneic immune response to iPSC-derived cells and isogeneic parental somatic cells used for reprogramming.MethodsWe established an isogeneic cell model consisting of parental dermal fibroblasts, fibroblast-like iPSC-derivatives (iPS-fibro) and iPS-fibro lacking beta-2-microglobulin (B2M). Using the cells obtained from two patients, we analyzed the activation of autologous and allogeneic T-lymphocytes and NK-cells co-cultured with target cells.ResultsHere we report that cells differentiated from iPSCs can be recognized by NK-cells rather than by autologous T-cells. We observed that iPS-fibro elicited a high level of NK-cell degranulation and cytotoxicity, while isogeneic parental skin fibroblasts used to obtain iPSCs barely triggered an NK-cell response. iPSC-derivatives with B2M knockout did not cause an additional increase in NK-cell activation, although they were devoid of HLA-I, the major inhibitory molecules for NK-cells. Transcriptome analysis revealed a significant imbalance of ligands for activating and inhibitory NK-cell receptors in iPS-fibro. Compared to parental fibroblasts, iPSC-derivatives had a reduced expression of HLA-I simultaneously with an increased gene expression of major activating ligands, such as MICA, NECTIN2, and PVR. The lack of inhibitory signals might be due to insufficient maturity of cells differentiated from iPSCs. In addition, we showed that pretreatment of iPS-fibro with proinflammatory cytokine IFNγ restored the ligand imbalance, thereby reducing the degranulation and cytotoxicity of NK-cells.ConclusionIn summary, we showed that iPSC-derived cells can be sensitive to the cytotoxic potential of autologous NK-cells regardless of HLA-I status. Thus, the balance of ligands for NK-cell receptors should be considered prior to iPSC-based cell therapies. Trial registration Not applicable.

Project description:Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease. Despite the wide use of conventional synthetic, targeted and biologic disease modifying anti-rheumatic drugs (DMARDs) to control its radiological progress, nearly all DMARDs are immunologically non-selective and do not address the underlying immunological mechanisms of RA. Patients with RA often need to take various DMARDs long-term or even lifelong and thus, face increased risks of infection, tumor and other adverse reactions. It is logical to modulate the immune disorders and restore immune balance in patients with RA by restoring immune tolerance. Indeed, approaches based on stem cell transplantation, tolerogenic dendritic cells (tolDCs), and antigen-based tolerogenic vaccination are under active investigation, and some have already transformed from wet bench research to clinical investigation during the last decade. Among them, clinical trials on stem cell therapy, especially mesenchymal stem cells (MSCs) transplantation are most investigated and followed by tolDCs in RA patients. On the other hand, despite active laboratory investigations on the use of RA-specific peptide-/protein-based tolerogenic vaccines for T cell, clinical studies on RA patients are much limited. Overall, the preliminary results of these clinical studies are promising and encouraging, demonstrating their safety and effectiveness in the rebalancing of T cell subsets; particular, the recovery of RA-specific Treg with increasing anti-inflammatory cytokines and reduced proinflammatory cytokines. Future studies should focus on the optimization of transplanted stem cells, the preparation of tolDCs, and tolerogenic vaccines with RA-specific protein or peptide, including their dosage, course, and route of administration with well-coordinated multi-center randomized clinical control researches. With the progress of experimental and clinical studies, generating and restoring RA-specific immune tolerance may bring revolutionary changes to the clinical management of RA in the near future.

Dataset Information

T-Cell Immune Imbalance in Rheumatoid Arthritis Is Associated with Alterations in NK Cells and NK-Like T Cells Expressing CD38.

Background

Methods

Results

Conclusions

Publications

T-Cell Immune Imbalance in Rheumatoid Arthritis Is Associated with Alterations in NK Cells and NK-Like T Cells Expressing CD38.

Similar Datasets

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