Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation

J Immunol. 2012 Feb 1;188(3):1206-12. doi: 10.4049/jimmunol.1102773. Epub 2011 Dec 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics*
  • Antigens, CD / physiology
  • CD28 Antigens
  • CD3 Complex / metabolism
  • Cell Differentiation
  • Humans
  • Interleukin-17 / biosynthesis
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / physiology
  • Signaling Lymphocytic Activation Molecule Family
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • T-Lymphocytes / pathology*
  • Th17 Cells / pathology*
  • Up-Regulation / genetics
  • Up-Regulation / physiology

Substances

  • Antigens, CD
  • CD28 Antigens
  • CD3 Complex
  • Interleukin-17
  • LY9 protein, human
  • Receptors, Antigen, T-Cell
  • Receptors, Cell Surface
  • SLAMF6 protein, human
  • Signaling Lymphocytic Activation Molecule Family
  • Signaling Lymphocytic Activation Molecule Family Member 1