title: Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance.
abstract: BACKGROUND
  Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) can mediate the function of SLAM molecules, which have been proposed to be involved in the development of autoimmunity in mice.
  
  
  OBJECTIVE
  We sought to determine whether the SLAM/SAP pathway regulates the establishment of human B-cell tolerance and what mechanisms of B-cell tolerance could be affected by SAP deficiency.
  
  
  METHODS
  We tested the reactivity of antibodies isolated from single B cells from SAP-deficient patients with X-linked lymphoproliferative disease (XLP). The expressions of SAP and SLAM family members were assessed in human bone marrow-developing B cells. We also analyzed regulatory T (Treg) cell function in patients with XLP and healthy control subjects.
  
  
  RESULTS
  We found that new emigrant/transitional B cells from patients with XLP were enriched in autoreactive clones, revealing a defective central B-cell tolerance checkpoint in the absence of functional SAP. In agreement with a B cell-intrinsic regulation of central tolerance, we identified SAP expression in a discrete subset of bone marrow immature B cells. SAP colocalized with SLAMF6 only in association with clustered B-cell receptors likely recognizing self-antigens, suggesting that SLAM/SAP regulate B-cell receptor-mediated central tolerance. In addition, patients with XLP displayed defective peripheral B-cell tolerance, which is normally controlled by Treg cells. Treg cells in patients with XLP seem functional, but SAP-deficient T cells were resistant to Treg cell-mediated suppression. Indeed, SAP-deficient T cells were hyperresponsive to T-cell receptor stimulation, which resulted in increased secretion of IL-2, IFN-γ, and TNF-α.
  
  
  CONCLUSIONS
  SAP expression is required for the counterselection of developing autoreactive B cells and prevents their T cell-dependent accumulation in the periphery.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Laurence
authors.initials: L
authors.lastname: Menard
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Tineke
authors.initials: T
authors.lastname: Cantaert
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.affiliation: Immunology Program, Garvan Institute of Medical Research, and St Vincent's Clinical School, University of New South Wales, Darlinghurst, Australia.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.affiliation: Department of Immunology, Concord Hospital, Sydney, Australia.
authors.forename: Sean
authors.initials: S
authors.lastname: Riminton
authors.affiliation: Divisions of Clinical Immunology and Allergy, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Church
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Amy
authors.initials: A
authors.lastname: Klion
authors.affiliation: Department of Medicine, Immunology Institute, Mt Sinai School of Medicine, New York, NY.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cunningham-Rundles
authors.affiliation: Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Conn. Electronic address: eric.meffre@yale.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D053264:B-Cell Activating Factor / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D053264:B-Cell Activating Factor; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; C000604060:SLAMF6 protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; C000604063:Slamf6 protein, mouse; C505719:TNFSF13B protein, human; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1
keywords: B-cell tolerance; SLAM-associated protein; regulatory T cells; signaling lymphocytic activation molecule