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Efficient Recruitment of Lymphocytes in Inflamed Brain Venules Requires Expression of Cutaneous Lymphocyte Antigen and Fucosyltransferase-VII¹

Laura Piccio^2,*,, Barbara Rossi^2,*, Lucia Colantonio, Roland Grenningloh, Andrea Gho, Linda Ottoboni^*, Jonathon W. Homeister, Elio Scarpini, Marianna Martinello^*, Carlo Laudanna^*, Daniele D’Ambrosio, John B. Lowe and Gabriela Constantin^3,*

^* Department of Pathology, University of Verona, Verona, Italy; Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; BioXell, Milan, Italy; and Howard Hughes Medical Institute, Life Sciences Institute and Department of Pathology, University of Michigan, Ann Arbor, MI 48109

Lymphocyte migration into the brain represents a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms controlling the recruitment of lymphocytes to the CNS via inflamed brain venules are poorly understood, and therapeutic approaches to inhibit this process are consequently few. In this study, we demonstrate for the first time that human and murine Th1 lymphocytes preferentially adhere to murine inflamed brain venules in an experimental model that mimics early inflammation during EAE. A virtually complete inhibition of rolling and arrest of Th1 cells in inflamed brain venules was observed with a blocking anti-P-selectin glycoprotein ligand 1 Ab and anti-E- and P-selectin Abs. Th1 lymphocytes produced from fucosyltransferase (FucT)-IV^–/– mice efficiently tethered and rolled, whereas in contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VII^–/– or Fuc-VII^–/–FucT-IV^–/– mice was drastically reduced, indicating that FucT-VII is critical for the recruitment of Th1 cells in inflamed brain microcirculation. Importantly, we show that Abs directed against cutaneous lymphocyte Ag (CLA), a FucT-VII-dependent carbohydrate modification of P-selectin glycoprotein ligand 1, blocked rolling of Th1 cells. By exploiting a system that allowed us to obtain Th1 and Th2 cells with skin- vs gut-homing (CLA⁺ vs integrin ₇⁺) phenotypes, we observed that induced expression of CLA on Th cells determined a striking increase of rolling efficiency in inflamed brain venules. These observations allow us to conclude that efficient recruitment of activated lymphocytes to the brain in the contexts mimicking EAE is controlled by FucT-VII and its cognate cell surface Ag CLA.

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