Defects in CD4+ T cell LFA‐1 integrin‐dependent adhesion and proliferation protect Cd47−/− mice from EAE

• Published in: Journal of leukocyte biology Vol. 101; no. 2; pp. 493 - 505
• Main Authors: Azcutia, Veronica, Bassil, Ribal, Herter, Jan M., Engelbertsen, Daniel, Newton, Gail, Autio, Anu, Mayadas, Tanya, Lichtman, Andrew H., Khoury, Samia J., Parkos, Charles A., Elyaman, Wassim, Luscinskas, Francis W.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.02.2017; John Wiley and Sons Inc
• Subjects: Adhesion; Adoptive Transfer; Animals; Antibodies, Monoclonal - pharmacology; Antigen Presentation - drug effects; Antigen Presentation - immunology; Auditory defects; autoimmune; CD28 Antigens - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD47 Antigen - metabolism; Cell activation; Cell adhesion; Cell Adhesion - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chemokines - pharmacology; Crosslinking; Defects; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - prevention & control; Experimental allergic encephalomyelitis; Female; Glycoproteins; Homeostasis; Humans; Immunization; Inflammation, Extracellular Mediators, & Effector Molecules; Integrin alpha4beta1 - metabolism; Integrins; Intercellular Adhesion Molecule-1 - metabolism; LFA-1 antigen; Lymph Nodes - drug effects; Lymph Nodes - pathology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Myelin; Myelin-Oligodendrocyte Glycoprotein - immunology; neuroinflammation; Oligodendrocyte-myelin glycoprotein; Receptors, Antigen, T-Cell - metabolism; T cell receptors; T lymphocytes; TCR activation; Vascular Cell Adhesion Molecule-1 - metabolism; VLA-4 antigen; T lymphocytes; TCR activation; autoimmune; neuroinflammation
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.3A1215-546RR

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.