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

Background Signaling lymphocytic activation molecule( SLAM)–associated protein (SAP) can mediate the function of SLAMmolecules, 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-celltolerance and what mechanisms of B-celltolerance could be affected by SAP deficiency. Methods We tested the reactivity of antibodies isolated from single B cellsfrom SAP-deficient patients with X-linked lymphoproliferative disease(XLP). The expressions of SAP and SLAMfamily 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 cellsfrom patients with XLP were enriched in autoreactive clones, revealing a defective central B-celltolerance 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 receptorslikely recognizing self-antigens, suggesting that SLAM/SAP regulate B-cell receptor–mediated central tolerance. In addition, patients with XLP displayed defective peripheral B-celltolerance, 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 cellsand prevents their T cell–dependent accumulation in the periphery.