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Sialomucin CD43 regulates Th17 cell ICAM-1 dependent adhesion, apical migration and transendothelial migration

Velzquez, FE;Anastasiou, M;Carrillo-Salinas, FJ;Ngwenyama, N;Salvador, AM;Nevers, T;Alcaide, P;

T helper type 17 lymphocytes (Th17 cells) infiltrate the central nervous system (CNS), induce inflammation and demyelination and play a pivotal role in the pathogenesis of multiple sclerosis (MS). Sialomucin CD43 is highly expressed in Th17 cells and mediates adhesion to endothelial selectin (E-selectin), an initiating step in Th17 cell recruitment to sites of inflammation. CD43-/- mice have impaired Th17 cell recruitment to the CNS and are protected from Experimental Autoimmune Encephalomyelitis (EAE), the mouse model of multiple sclerosis. However, E-selectin is dispensable for the development of EAE, in contrast to intercellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). We report that CD43-/- mice have decreased demyelination and T cell infiltration, but similar upregulation of ICAM-1 and VCAM-1 in the spinal cord, as compared to WT mice, at the initiation of EAE. CD43-/- Th17 cells have impaired adhesion to ICAM-1 under flow conditions in vitro, despite having similar expression of LFA-1, the main T cell ligand for ICAM-1, as WT Th17 cells. Regardless of the route of integrin activation, CD43-/- Th17 cells firm arrest on ICAM-1 was comparable to WT Th17 cells, but CD43-/- Th17 cells failed to optimally apically migrate on immobilized ICAM-1 coated coverslips and endothelial cells, and to transmigrate under shear flow conditions in an ICAM-1 dependent manner. Collectively, these findings unveil novel roles for CD43, facilitating adhesion of Th17 cells to ICAM-1 and modulating apical and transendothelial migration, as mechanisms potentially responsible for Th17 cell recruitment to sites of inflammation such as the CNS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.