ROLE OF SH2D1A/SAP IN NKT CELL DEVELOPMENT AND FUNCTION

SH2D1A/SAP 在 NKT 细胞发育和功能中的作用

• 批准号: 6987827
• 负责人: KIM Erika NICHOLS
• 金额: $ 20.26万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987827
• 关键词: CD antigens; biological signal transduction; cell differentiation; cell population study; clinical research; cytogenetics; cytology; genetically modified animals; human subject; inborn immunodeficiency; laboratory mouse; leukocyte activation /transformation; natural killer cells; phenotype; protein structure function; receptor expression

DESCRIPTION (provided by applicant): The Src homology 2 domain-containing gene 1A (SH2D1A) encodes an adaptor molecule known as SAP that is defective in patients with X-linked lymphoproliferative disease (XLP), a disorder associated with abnormal antiviral and antitumor immunity. SAP is expressed in T cells and Natural Killer (NK) cells, where it regulates Thl and Th2 cytokine production, as well as cytotoxic function. To determine whether SAP controls the activity of NKT cells, a lymphocyte subset sharing features with T and NK cells, we examined SAP -/- mice and human XLP patients for the presence of this lineage. Remarkably, NKT cells were dramatically reduced or absent, suggesting that, in addition to its essential role in mature T and NK cells, SAP is required for NKT cell development. Consistent with the lack of NKT cells, SAP -/- mice failed to upregulate cytokines in response to a-galactosyl ceramide, a glycolipid antigen that specifically activates these cells. Based on these new findings, we hypothesize that SAP is a critical signaling molecule that is required for coordinating the biochemical pathways controlling NKT cell ontogeny. We also propose that the severe reduction in NKT cells, when combined with abnormally functioning T and NK cells, contributes to the pathogenesis of XLP. In this proposal, we aim to rigorously dissect the role of SAP during NKT cell development and mature NKT cell activation. To firmly establish whether SAP is required during human NKT cell differentiation, in Aim 1 we will use cell-based and molecular assays to evaluate NKT cell number in a larger spectrum of patients with XLP and related immunological defects. In Aim 2, we will study whether SAP is required for mature NKT cell function. After reconstituting NKT cell development in SAP -/- mice, WT and SAP -/-cells will be investigated using in vitro and in vivo assays. Structure-function analyses in Aim 3 will define how the domains within SAP mediate its participation in NKT cell signaling. These investigations will increase our understanding of NKT cell development and may enable the design of new treatments for XLP or other human diseases associated with quantitative or qualitative NKT cell defects, including immunodeficiency, autoimmunity and cancer.

描述（由申请人提供）：SRC同源性2含结构域的基因1a（SH2D1A）编码一种称为SAP的衔接子分子，称为SAP，在患有X-连接淋巴细胞学疾病（XLP）的患者中有缺陷，这种疾病与异常抗病毒和抗体免疫相关。 SAP在T细胞和天然杀伤（NK）细胞中表达，它调节THL和Th2细胞因子的产生以及细胞毒性功能。为了确定SAP是否控制着NKT细胞的活性，与T和NK细胞的淋巴细胞子集共享特征，我们检查了SAP - / - 小鼠和人XLP患者是否存在这种谱系。值得注意的是，NKT细胞大大降低或不存在，这表明除了其在成熟T和NK细胞中的重要作用外，SAP还需要NKT细胞发育。与缺乏NKT细胞一致，SAP - / - 小鼠无法响应A-半乳糖基酰胺（一种专门激活这些细胞）的A-半乳糖基酰胺，无法上调细胞因子。基于这些新发现，我们假设SAP是一个关键的信号分子，是协调控制NKT细胞个体发育的生化途径所必需的。我们还建议，当与异常功能的T和NK细胞结合时，NKT细胞的严重降低有助于XLP的发病机理。在此提案中，我们旨在严格剖析SAP在NKT细胞发育和成熟NKT细胞激活中的作用。为了牢固确定在人类NKT细胞分化过程中是否需要SAP，在AIM 1中，我们将使用基于细胞的和分子测定法来评估较大的XLP患者和相关免疫缺陷患者中NKT细胞的数量。在AIM 2中，我们将研究是否需要成熟的NKT细胞功能SAP。在重构SAP - / - 小鼠，WT和SAP - / - 细胞中的NKT细胞发育后，将使用体外和体内测定进行研究。 AIM 3中的结构 - 功能分析将定义SAP中的域如何介导其参与NKT细胞信号。这些研究将增加我们对NKT细胞发育的理解，并可以设计与定量或定性NKT细胞缺陷有关的XLP或其他人类疾病的新治疗方法，包括免疫缺陷，自身免疫性和癌症。

项目成果

Lymphocytic vasculitis involving the central nervous system occurs in patients with X-linked lymphoproliferative disease in the absence of Epstein-Barr virus infection.

• DOI: 10.1002/pbc.22185
• 发表时间: 2009-12
• 期刊: PEDIATRIC BLOOD & CANCER
• 影响因子: 3.2
• 作者: Talaat, Kawsar R.;Rothman, Jennifer A.;Cohen, Jeffrey I.;Santi, Mariarita;Choi, John K.;Guzman, Miguel;Zimmerman, Robert;Nallasamy, Sudha;Brucker, Alexander;Quezado, Martha;Pittaluga, Stefania;Patronas, Nicholas J.;Klion, Amy D.;Nichols, Kim E.
• 通讯作者: Nichols, Kim E.

Differential requirement for the SAP-Fyn interaction during NK T cell development and function.

• DOI: 10.4049/jimmunol.181.4.2311
• 发表时间: 2008-08-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Nunez-Cruz S;Yeo WC;Rothman J;Ojha P;Bassiri H;Juntilla M;Davidson D;Veillette A;Koretzky GA;Nichols KE
• 通讯作者: Nichols KE