title: LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling-Dependent Notch Pathway.
abstract: In this study, we report that the integrin LFA-1 cross-linking with its ligand ICAM-1 in human PBMCs or CD4(+) T cells promotes Th1 polarization by upregulating IFN-γ secretion and T-bet expression. LFA-1 stimulation in PBMCs, CD4(+) T cells, or the T cell line HuT78 activates the Notch pathway by nuclear translocation of cleaved Notch1 intracellular domain (NICD) and upregulation of target molecules Hey1 and Hes1. Blocking LFA-1 by a neutralizing Ab or specific inhibition of Notch1 by a γ-secretase inhibitor substantially inhibits LFA-1/ICAM-1-mediated activation of Notch signaling. We further demonstrate that the Notch pathway activation is dependent on LFA-1/ICAM-1-induced inactivation of glycogen synthase kinase 3β (GSK3β), which is mediated via Akt and ERK. Furthermore, in silico analysis in combination with coimmunoprecipitation assays show an interaction between NICD and GSK3β. Thus, there exists a molecular cross-talk between LFA-1 and Notch1 through the Akt/ERK-GSK3β signaling axis that ultimately enhances T cell differentiation toward Th1. Although clinical use of LFA-1 antagonists is limited by toxicity related to immunosuppression, these findings support the concept that Notch inhibitors could be attractive for prevention or treatment of Th1-related immunologic disorders and have implications at the level of local inflammatory responses.
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921; Singapore Eye Research Institute, Singapore 168751; nkverma@ntu.edu.sg.
authors.forename: Navin K
authors.identifier: 0000-0002-5940-6633
authors.initials: NK
authors.lastname: Verma
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: M H U Turabe
authors.identifier: 0000-0002-4621-8625
authors.initials: MH
authors.lastname: Fazil
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: Seow Theng
authors.initials: ST
authors.lastname: Ong
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: Madhavi Latha S
authors.identifier: 0000-0002-3883-8664
authors.initials: ML
authors.lastname: Chalasani
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: Jian Hui
authors.identifier: 0000-0003-4268-2460
authors.initials: JH
authors.lastname: Low
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: Amuthavalli
authors.identifier: 0000-0002-6530-0448
authors.initials: A
authors.lastname: Kottaiswamy
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: Praseetha
authors.initials: P
authors.lastname: P
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: Atish
authors.identifier: 0000-0003-1686-6063
authors.initials: A
authors.lastname: Kizhakeyil
authors.affiliation: Institute of Life Sciences, Bhubaneshwar, Odisha 751023, India;
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Centre for Life Sciences, Central University of Jharkhand, Ranchi 835205, India;
authors.forename: Aditya K
authors.initials: AK
authors.lastname: Panda
authors.affiliation: Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland;
authors.forename: Michael
authors.initials: M
authors.lastname: Freeley
authors.affiliation: Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland; School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland; and.
authors.forename: Sinead M
authors.identifier: 0000-0003-3460-3590
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921;
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921; Faculty of Medicine, University of British Columbia, Vancouver, British Columbia V1Y 1T3, Canada.
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
mesh_terms: D056704:Adaptive Immunity; D019138:Antibodies, Blocking / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology*; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D019138:Antibodies, Blocking; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C485631:HEY1 protein, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human