Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Menard, Laurence¹  Cantaert, Tineke¹  Chamberlain, Nicolas¹  Tangye, Stuart G.^2,3  Riminton, Sean⁴  Church, Joseph A.^5,6  Klion, Amy⁷  Cunningham-Rundles, Charlotte⁸  Nichols, Kim E.⁹  Meffre, Eric¹ 

[1] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06511 USA

[2] Univ New S Wales, Garvan Inst Med Res, Program Immunol, Darlinghurst, NSW, Australia

[3] Univ New S Wales, St Vincents Clin Sch, Darlinghurst, NSW, Australia

[4] Concord Hosp, Dept Immunol, Sydney, NSW, Australia

[5] Univ So Calif, Childrens Hosp Los Angeles, Div Clin Immunol & Allergy, Los Angeles, CA USA

[6] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA

[7] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA

[8] Mt Sinai Sch Med, Inst Immunol, Dept Med, New York, NY USA

[9] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

关键词: SLAM-associated protein;    signaling lymphocytic activation molecule;    B-cell tolerance;    regulatory T cells;   

DOI  :  10.1016/j.jaci.2013.10.051

来源: Elsevier

【 摘 要 】

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-gamma, and TNF-alpha. Conclusions: SAP expression is required for the counterselection of developing autoreactive B cells and prevents their T cell-dependent accumulation in the periphery.

【 授权许可】

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