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CD147 Expressed on Memory CD4+ T Cells Limits Th17 Responses in Patients With Rheumatoid Arthritis.

ABSTRACT: Rheumatoid arthritis (RA) is a common autoimmune disease in which T helper-type 17 (Th17) cells have been critically involved. CD147 is a T cell activation-associated molecule and is involved in T cell development. However, it remains unclear whether CD147 participates in Th17 responses in RA patients. In this study, we demonstrated that in both the RA and healthy controls (HC) groups, CD147 expression on CD4+ T cells was increased in CCR6+ and CD161+ subsets, and was associated with IL-17 production. Ligation of CD147 with its monoclonal antibody (mAb) strongly inhibited Th17 responses, and knock down of CD147 expression on CD4+ Tm cells specifically enhanced Th17 responses, triggered by coculture with in vitro activated monocytes from HC. Further functional studies showed that anti-CD147 mAb decreased the activation of AKT, mTORC1 and STAT3 signaling, which is known to enhance Th17 responses. Ligation of CD147 with its mAb on CD4+ Tm cells specifically reduced Th17 responses induced by in vitro or in vivo activated monocytes from RA patients. In collagen-induced arthritis model, anti-CD147 mAb treatment reduced the Th17 levels and severity of arthritis in vivo. These data suggest that CD147 plays a negative role in regulating human Th17 responses. Anti-CD147 mAb can limit the extraordinary proliferation of Th17 cells and may be a new therapeutic option in RA.

SUBMITTER: Miao J

PROVIDER: S-EPMC7655988 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CD147 Expressed on Memory CD4+ T Cells Limits Th17 Responses in Patients With Rheumatoid Arthritis.

Miao Jinlin J Zhang Kui K Zheng Zhaohui Z Zhang Rui R Lv Minghua M Guo Na N Xu Yingming Y Han Qing Q Chen Zhinan Z Zhu Ping P

Frontiers in immunology 20201028

Rheumatoid arthritis (RA) is a common autoimmune disease in which T helper-type 17 (Th17) cells have been critically involved. CD147 is a T cell activation-associated molecule and is involved in T cell development. However, it remains unclear whether CD147 participates in Th17 responses in RA patients. In this study, we demonstrated that in both the RA and healthy controls (HC) groups, CD147 expression on CD4+ T cells was increased in CCR6+ and CD161+ subsets, an ...[more]

PMID: 33193313

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Project description:IntroductionAccumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway.MethodsWe analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva.ResultsCompared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70).ConclusionsRA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.

Project description:BackgroundThe genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis.ResultMonocytes, naïve and memory CD4+ T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4+ T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4+ T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4+ T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively.ConclusionOur data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.

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CD147 Expressed on Memory CD4+ T Cells Limits Th17 Responses in Patients With Rheumatoid Arthritis.

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CD147 Expressed on Memory CD4<sup>+</sup> T Cells Limits Th17 Responses in Patients With Rheumatoid Arthritis.

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