Underexpression of TIM-3 and Blunted Galectin-9-Induced Apoptosis of CD4+ T Cells in Rheumatoid Arthritis

Abstract

The aim of this study is to compare the expression of TIM-3 from CD4+ T cells from rheumatoid arthritis (RA) patients and healthy controls and to evaluate the effect of galectin-9 (Gal-9) on apoptosis of CD4+ T cells in these patients. CD4+ T cells from RA patients and healthy controls were isolated from peripheral blood mononuclear cells and were activated. The expression of TIM-3 mRNA in CD4+ T cells was measured using real-time polymerase chain reaction. CD4+ T cells were activated in the presence of graded doses of Gal-9 or control, and Gal-9-induced cytotoxicity and apoptotic activity of CD4+ T cells were analyzed using MTT assays and annexin-V staining, respectively. TIM-3 mRNA expression was significantly lower in CD4+ T cells from RA patients compared with those in healthy controls (p = 0.028). CD4+ T cell survival as measured by MTT assay when incubated with Gal-9 (15 nM) was significantly higher in RA patients than in healthy controls (p = 0.002). Apoptotic activity of CD4+ T cells from healthy controls as measured by annexin staining increased with graded doses of Gal-9 (0 nM vs. 30 nM, 0 nM vs. 90 nM, p = 0.016 each). However, apoptotic activity of CD4+ T cells from RA patients did not change despite the stimulation with Gal-9. Gal-9-mediated apoptosis of CD4+ T cells is dysfunctional in RA patients. Blunted Gal-9-mediated apoptosis may be exerted through underexpression of TIM-3 that negatively regulates Th1 response. Our data suggest that TIM-3 and its interaction with Gal-9 may play an important role in the pathogenesis of RA and may represent a potential therapeutic target.

A novel monoclonal antibody for detection of galectin-9 in tissue sections: application to human tissues infected by oncogenic viruses

“…For example, the Tim-3 receptor on CD4+ Th1 clones from patients with multiple sclerosis (MS) is defective in its response to galectin-9 [7,8]. Similar results were reported for patients with rheumatoid arthritis and recently auto-immune hepatitis [9,10]. Reciprocally, there is evidence of excessive galectin-9 production in two human diseases associated with oncogenic viruses : nasopharyngeal carcinomas (NPC) associated with the Epstein-Barr virus (EBV) and chronic infection by the hepatitis C virus (HCV) [11,12].…”

Functional Annotation of Rheumatoid Arthritis and Osteoarthritis Associated Genes by Integrative Genome-Wide Gene Expression Profiling Analysis

“…Specifically, the top deregulated genes for OA vs. NT samples include the DPM2, MUS81, VAMP2, ZBTB33, NUP62, RHBDD1, PDZD7, PLEKHG4, ABCG1, TCEA3, etc. Several of these genes have been identified to be involved in the development RA or OA samples, including COL2 [24], Gal-9 [25], [26], MUS81 [27] and ABCG1 [28].…”

TIM polymorphisms—genetics and function

“…TIM-3 expression was upregulated in peripheral monocytes and T cells, and synovial tissue in RA patients. In addition, TIM-3 expression on PBMC, T cells, and NKT cells was inversely correlated with plasma TNF-α levels and disease severity 4849 . Chae et al investigated genotype and allele frequencies of three TIM-3 polymorphisms in RA patients 50 .…”