Nature Medicine
11, 340 - 345 (2005)
Published online: 13 February 2005; | doi:10.1038/nm1189
Regulation of NKT cell development by SAP, the protein defective in XLPKim E Nichols1, 2, Jamie Hom2, Shun-You Gong3, Arupa Ganguly4, Cindy S Ma5, Jennifer L Cannons6, Stuart G Tangye5, Pamela L Schwartzberg6, Gary A Koretzky2, 7
& Paul L Stein3, 81
Pediatric Oncology, Wood, 4th floor, 3615 Civic Center Boulevard, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. 2
Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III, Room 415, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. 3
Department of Dermatology, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. 4
Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. 5
Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag #6, Newtown, NSW 2014, Australia. 6
National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4A38, 49 Convent Drive, MSC 4472, Bethesda, Maryland, USA. 7
Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. 8
Present address: Dermatology and Microbiology-Immunology, Ward 9-003, Northwestern University School of Medicine, 303 E. Chicago Avenue, Chicago, Illinois 60611, USA.
Correspondence should be addressed to Kim E Nichols nicholsk@email.chop.edu or Paul L Stein p-stein2@northwestern.eduThe 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  -galactosyl ceramide (GC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell−dependent manner. While evaluating the abnormalities in GC-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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