title: Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation.
abstract: Altered T cell function in systemic lupus erythematosus (SLE) is determined by various molecular and cellular abnormalities, including increased IL-17 production. Recent evidence suggests a crucial role for signaling lymphocyte activation molecules (SLAMs) in the expression of autoimmunity. In this study, we demonstrate that SLAMF3 and SLAMF6 expression is increased on the surface of SLE T cells compared with normal cells. SLAM coengagement with CD3 under Th17 polarizing conditions results in increased IL-17 production. SLAMF3 and SLAMF6 T cell surface expression and IL-17 levels significantly correlate with disease activity in SLE patients. Both naive and memory CD4(+) T cells produce more IL-17 in response to SLAM costimulation as compared with CD28 costimulation. In naive CD4(+) cells, IL-17 production after CD28 costimulation peaks on day 3, whereas costimulation with anti-SLAMF3 and anti-SLAMF6 Abs results in a prolonged and yet increasing production during 6 d. Unlike costimulation with anti-CD28, SLAM costimulation requires the presence of the adaptor molecule SLAM-associated protein. Thus, engagement of SLAMF3 and SLAMF6 along with Ag-mediated CD3/TCR stimulation represents an important source of IL-17 production, and disruption of this interaction with decoy receptors or blocking Abs should mitigate disease expression in SLE and other autoimmune conditions.
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Madhumouli
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Toth
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology; D018106:CD28 Antigens; D017252:CD3 Complex / Q000378:metabolism; D002454:Cell Differentiation; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013601:T-Lymphocytes / Q000473:pathology*; D058504:Th17 Cells / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D015703:Antigens, CD; D018106:CD28 Antigens; D017252:CD3 Complex; D020381:Interleukin-17; C430423:LY9 protein, human; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; C000604060:SLAMF6 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1