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

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.