Regulation of NKT Cell Development by Sap, the Adaptor Mutated in X-Linked Lymphoproliferative Disease.

Abstract

The adaptor molecule SAP is expressed in T and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity. Here we demonstrate that SAP also plays a critical role during NKT cell development. Sap−/− mice lack thymic and peripheral NKT cells and fail to produce cytokines in response to the NKT cell stimulus alpha-galactosyl ceramide. Infection of Sap−/− bone marrow cells with retroviruses expressing wild-type SAP permits NKT cell development after transfer into irradiated recipients. X-linked lymphoproliferative disease (XLP) patients, who harbor germline mutations in the gene encoding SAP, also lack NKT cells. Furthermore, a female XLP carrier demonstrates completely skewed X chromosome inactivation within peripheral blood NKT cells, but not T or B cells. Thus, SAP is a critical regulator of NKT cell ontogeny in humans and in mice. The absence of this cell lineage may contribute to the phenotypes of XLP, including abnormal anti-viral and anti-tumor immunity and hypogammaglobulinemia.

Missense mutations in SH2D1A identified in patients with X-linked lymphoproliferative disease differentially affect the expression and function of SAP

“…Mononuclear cells (MNCs) were isolated from peripheral blood of normal healthy donors and XLP patients by centrifuging diluted whole blood over Ficoll-Paque (Amersham Biosciences, Uppsala, Sweden). The clinical manifestations of some of the XLP patients examined in this study, as well as several aspects of lymphocyte development, have been described previously (31)(32)(33). The effects of SH2D1A mutations on expression of SAP in patients XLP#1, 2 and 3 have been published (14,34).…”