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A critical epitope in CD147 facilitates memory CD4+ T-cell hyper-activation in rheumatoid arthritis.

ABSTRACT: The abnormal activation of CD4+CD45RO+ memory T (Tm) cells plays an important role in the pathogenesis of rheumatoid arthritis (RA). Previous studies have shown that CD147 participates in T-cell activation. However, it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients. In this study, we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients. The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis. Using a structural-functional approach, we depicted the interface between 5A12 and CD147. This allowed us to identify two critical residues, Lys63 and Asp65, as potential targets for RA treatment, as the double mutation K63A/D65A inhibited Tm-cell activation, mimicking the neutralization by 5A12. This study provides not only a theoretical basis for a "CD147-Tm/Osteoclast-RA chain" for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.

SUBMITTER: Guo N

PROVIDER: S-EPMC6804595 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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A critical epitope in CD147 facilitates memory CD4+ T-cell hyper-activation in rheumatoid arthritis.

Guo Na N Ye Sheng S Zhang Kui K Yu Xiaoling X Cui Hongyong H Yang Xiangmin X Lin Peng P Lv Minghua M Miao Jinlin J Zhang Yang Y Han Qing Q Zhang Rongguang R Chen Zhinan Z Zhu Ping P

Cellular & molecular immunology 20180321 6

The abnormal activation of CD4+CD45RO+ memory T (Tm) cells plays an important role in the pathogenesis of rheumatoid arthritis (RA). Previous studies have shown that CD147 participates in T-cell activation. However, it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients. In this study, we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients. The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activ ...[more]

PMID: 29563614

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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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A critical epitope in CD147 facilitates memory CD4+ T-cell hyper-activation in rheumatoid arthritis.

Publications

A critical epitope in CD147 facilitates memory CD4<sup>+</sup> T-cell hyper-activation in rheumatoid arthritis.

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