Immunology

Biography

Biography: Navin K Verma

Abstract

Introduction: The T-cell integrin LFA-1 interacts with the ligand ICAM-1 expressed on endothelium and this interaction is important in T-cell motility. But downstream signalling pathways triggered by LFA-1/ICAM-1 ligation in T-cells are not clear. Here, we show that LFA-1-signalling for T-cell migration modulates gene expression, induces notch and TGF-β pathways and influences T-cell differentiation. Methods: Primary human T-cells or T-cell line Hut78 were stimulated via LFA-1 by incubating on immobilised recombinant ICAM-1. Standard molecular, biochemical and imaging techniques including Affymetrix Gene Chip® microarrays, real-time PCR, Western-immunoblotting, siRNA, confocal microscopy and high content analysis were utilized. Results: LFA-1/ICAM-1 ligation in T-cells induced genomic signatures associated with Notch and TGF-β pathways. We verified the activation of notch signalling by nuclear translocation of its cleaved intracellular domain and up-regulation of target genes Hey1 and Hes1. Moreover, a subset of molecules associated with reduced TGF-β responsiveness including Smad7, Smurf2 and Ski were found to be up-regulated, which was dependent of Stat3 and/or JNK activation. While LFA-1/ICAM-1 promoted Notch-dependent Tbet+ Th1 polarization, LFA-1-stimulated T-cells were refractory to TGF-β-mediated induction of Foxp3+ iTreg or RORγt+ Th17 differentiation. Pre-treatment of cells with blocking anti-LFA-1 antibody, specific inhibitors or siRNA against identified molecules substantially suppressed LFA-1-mediated modulation of T-cell functional phenotypes. Conclusion: We demonstrate a novel mechanism by which LFA-1/ICAM-1 ligation regulates immune response through notch and TGF-β pathways concurrent with its role in T-cell migration. These new findings have implications for normal immunologic functions and may also have therapeutic relevance for immune-mediated diseases.