Journal
JOURNAL OF IMMUNOLOGY
Volume 191, Issue 7, Pages 3673-3680Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1300945
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Funding
- National Multiple Sclerosis Society Collaborative Research Center Award [CA1061-A-18]
- National Institutes of Health [P01 AI045757, U19AI046130, U19 AI070352, P01 AI039671]
- National Institute of Neurological Disorders and Stroke [NS2427]
- Nancy Taylor Foundation for Chronic Diseases Inc.
- Ministerio de Educacion y Ciencia-Becas MEC/Fulbright y Catedras Principe de Asturias-Plan Nacional de I-D+I
- Postdoctoral Scholarship in the Beatriu de Pinos Programme (Agencia de Gestio d'Ajuts Universitaris i de Recerca-Government of Catalonia, Spain)
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CD226 costimulatory signals strongly promote Th1 differentiation, enhancing IFN-gamma 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-gamma 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-gamma-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-gamma 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.
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