title: Regulation of NKT cell development by SAP, the protein defective in XLP.
abstract: The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity. 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 disease. Following stimulation with the NKT cell-specific agonist alpha-galactosyl ceramide (alphaGC), Sh2d1a-/- splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in alphaGC-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.
authors.affiliation: Pediatric Oncology, Wood, 4th floor, 3615 Civic Center Boulevard, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.forename: Jamie
authors.initials: J
authors.lastname: Hom
authors.forename: Shun-You
authors.initials: SY
authors.lastname: Gong
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cannons
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.forename: Gary A
authors.initials: GA
authors.lastname: Koretzky
authors.forename: Paul L
authors.initials: PL
authors.lastname: Stein
mesh_terms: D000818:Animals; D041321:Chromosomes, Human, X; D016207:Cytokines / Q000096:biosynthesis; D004303:Dosage Compensation, Genetic; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D007694:Killer Cells, Natural / Q000502:physiology*; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D051379:Mice; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein