title: Defects in CD4+ T cell LFA-1 integrin-dependent adhesion and proliferation protect Cd47-/- mice from EAE.
abstract: CD47 is known to play an important role in CD4+T cell homeostasis. We recently reported a reduction in mice deficient in the Cd47 gene (Cd47-/-) CD4+T cell adhesion and transendothelial migration (TEM) in vivo and in vitro as a result of impaired expression of high-affinity forms of LFA-1 and VLA-4 integrins. A prior study concluded that Cd47-/-mice were resistant to experimental autoimmune encephalomyelitis (EAE) as a result of complete failure in CD4+T cell activation after myelin oligodendrocyte glycoprotein peptide 35-55 aa (MOG35-55) immunization. As the prior EAE study was published before our report, authors could not have accounted for defects in T cell integrin function as a mechanism to protect Cd47-/-in EAE. Thus, we hypothesized that failure of T cell activation involved defects in LFA-1 and VLA-4 integrins. We confirmed that Cd47-/-mice were resistant to MOG35-55-induced EAE. Our data, however, supported a different mechanism that was not a result of failure of CD4+T cell activation. Instead, we found that CD4+T cells in MOG35-55-immunized Cd47-/-mice were activated, but clonal expansion contracted within 72 h after immunization. We used TCR crosslinking and mitogen activation in vitro to investigate the underlying mechanism. We found that naïve Cd47-/-CD4+T cells exhibited a premature block in proliferation and survival because of impaired activation of LFA-1, despite effective TCR-induced activation. These results identify CD47 as an important regulator of LFA-1 and VLA-4 integrin-adhesive functions in T cell proliferation, as well as recruitment, and clarify the roles played by CD47 in MOG35-55-induced EAE.
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Azcutia
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ribal
authors.initials: R
authors.lastname: Bassil
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Herter
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Engelbertsen
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Newton
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Autio
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Mayadas
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Abou Haidar Neuroscience Institute, American University of Beirut, Lebanon; and.
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; elyaman@rics.bwh.harvard.edu.
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; fluscinskas@partners.org.
authors.forename: Francis W
authors.initials: FW
authors.lastname: Luscinskas
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051928:CD47 Antigen / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007114:Immunization; D039041:Integrin alpha4beta1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D051928:CD47 Antigen; D018925:Chemokines; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D063308:Myelin-Oligodendrocyte Glycoprotein; D011948:Receptors, Antigen, T-Cell; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1
keywords: T lymphocytes; TCR activation; autoimmune; neuroinflammation