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Regulation of NKT cell development by SAP, the protein defective in XLP


The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity1,2,3. Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease4. Following stimulation with the NKT cell–specific agonist α-galactosyl ceramide (αGC), Sh2d1a−/− splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell–dependent manner. While evaluating the abnormalities in αGC-induced immune responses, we observed that Sh2d1a−/− animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a−/− bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.

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Figure 1: Absence of αGC induced immune cell activation in Sh2d1a−/− mice.
Figure 2: Sh2d1a−/− mice lack NKT cells.
Figure 3: The defect in NKT cell ontogeny is hematopoietic cell-autonomous and rescued by expression of wild-type SAP.
Figure 4: XLP patients have reduced NKT cells and a female XLP carrier shows skewed X chromosome inactivation in NKT cells.


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We thank the patients who participated in this study. We are also grateful to R. Buckley, L. Silverman, A. Malbran, G. Uzel, S. Adelstein, R. Walls, F. Alvaro and D. Anderson for providing patient samples. We thank A. Bendelac for providing the Cd1d1−/− mice, W. Pear for the MIGR vector, M. Kronenberg and L. Sidobre for the αGC-loaded tetramer and the NKT cell hybridoma, L. Lanier for the Ly49D and Ly49G2 antibodies and Kirin Brewery for αGC. We acknowledge X. Zhong, M. Weiss, V. Shapiro and J. Stadanlick for their review of this manuscript, G. Bunin for assistance with statistics, and S. Jain for his technical assistance. This work was supported by the American Society of Hematology (K.E.N.), the Juvenile Diabetes Foundation, International (P.L.S.), the US National Institutes of Health (K.E.N., P.L.S.), the New South Wales Cancer Council (S.G.T.) and the University of Sydney, Australia (C.S.M.).

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Correspondence to Kim E Nichols or Paul L Stein.

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Supplementary Fig. 1

Sap−/− mice have normal numbers of T and NK cells. (PDF 88 kb)

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Nichols, K., Hom, J., Gong, SY. et al. Regulation of NKT cell development by SAP, the protein defective in XLP. Nat Med 11, 340–345 (2005).

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