The CD226/CD155 interaction regulates the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance in humans

• Published in: The Journal of immunology (1950) 2013-10, Vol.191 (7), p.3673-3680
• Main Authors: Lozano, Ester, Joller, Nicole, Cao, Yonghao, Kuchroo, Vijay K, Hafler, David A
• Format: Article
• Language: English
• Subjects: Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - metabolism; Cells, Cultured; Cytokines - biosynthesis; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Inflammation - immunology; Inflammation - metabolism; Lymphocyte Activation - immunology; Protein Binding - immunology; Receptors, Virus - genetics; Receptors, Virus - metabolism; Signal Transduction; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; Th2 Cells - immunology; Th2 Cells - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300945

CD226 costimulatory signals strongly promote Th1 differentiation, enhancing IFN-γ production by naive T cells. We recently reported that knockdown of CD226 on human T cells resulted in a decrease in T-bet and IFN-γ expression. However, the role of CD226 on Th2 and Th17 cells remains unknown. In this study, we found that CD226 and its ligand CD155 were decreased on Th2-polarized naive T cells, whereas both were highly expressed under Th17 conditions. Most IFN-γ- and IL-17-producing cells expressed high levels of CD226, but production of IL-13 did not correlate with CD226 expression. CD226 knockdown by lentiviral transduction resulted in increased STAT-6 phosphorylation, enhanced GATA3 expression, and consequently higher production of IL-4 and IL-13. Under Th17 conditions, CD226-depleted cells showed slightly impaired IL-17 secretion, suggesting that CD226 contributes, in part, to IL-17 production but is dispensable for Th17 cell generation. In line with these results, CD226 blockade with neutralizing Abs efficiently inhibited T cell activation and proliferation and production of IFN-γ and IL-17, whereas IL-13 secretion remained functional. Taken together, our results establish an important role for CD226 in differentially regulating the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance, suggesting that the CD226/CD155 interaction could potentially be targeted in therapeutic approaches to human autoimmune diseases.