title: CD6 as a potential target for treating multiple sclerosis.
abstract: CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating MS and potentially other T-cell-driven autoimmune conditions.
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Yan
authors.identifier: 0000-0002-7058-3569
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine and Pediatrics, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH 44109.
authors.forename: Nora G
authors.initials: NG
authors.lastname: Singer
authors.affiliation: Department of Medicine and Pediatrics, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH 44109.
authors.forename: Joy
authors.initials: J
authors.lastname: Whitbred
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bowen
authors.affiliation: Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI 48109.
authors.forename: David A
authors.identifier: 0000-0002-0230-6607
authors.initials: DA
authors.lastname: Fox
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; linf2@ccf.org.|College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology* / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C062279:CD6 antigen
keywords: CD6; EAE; multiple sclerosis