CD45 REGULATION OF T LYMPHOCYTE ACTIVATION

CD45 对 T 淋巴细胞激活的调节

• 批准号: 6632003
• 负责人: DAVID LEITENBERG
• 金额: $ 17.67万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632003
• 关键词: CD antigens; T cell receptor; biological signal transduction; calcium flux; cell differentiation; cytokine; helper T lymphocyte; leukocyte activation /transformation; phosphorylation; protein biosynthesis; protein tyrosine kinase; receptor binding; tissue /cell culture

DESCRIPTION (Adapted from Investigator's Abstract): Ligation of the T cell antigen receptor (TcR) does not result in a single series of events but rather can lead to a wide variety of different outcomes including proliferation, cytotoxicity, apoptosis, distinct patterns Of lymphokine secretion, and anergy. The precise mechanisms responsible for regulating these different outcomes remain unclear. One molecule important in regulating T cell activation is CD45, a family of high molecular weight transmembrane glycoproteins consisting of a cytoplasmic tail containing protein tyrosine phosphatase activity, and a variable external domain encoded in three exons which are differentially expressed due to post-transcriptional alternative RNA splicing, resulting in the expression of at least eight different isoforms. CD45 isoform expression on T lymphocytes is differentially regulated during thymic development and peripheral T cell activation and differentiation, and correlates with distinct effector functions. This suggests the hypothesis that the ectodomain of CD45 can regulate T cell signaling pathways during antigen activation. In support of this hypothesis is the observation that cells that express low molecular weight CD45 isoforms exhibit increased responsiveness to antigen signaling compared to cells expressing high molecular weight isoforms, and that this correlates with the ability of individual low molecular weight CD45 isoforms to associate with the CD4/T cell receptor complex. We hypothesize that the different ectodomain isoforms of CD45 may regulate substrate access to the tyrosine phosphatase domains by targeting CD45 to distinct areas in the membrane where it can associate with other molecules important in T cell signal transduction, altering their phosphorylation status and modifying the TcR signal transduction pathway. Using a combination of biochemical and genetic approaches in transfected T cell lines and in primary CD4 T cells, the investigator will address the following issues in this proposal: 1. The regulation and mechanism of CD45 association with the T cell receptor complex; and 2. The biochemical and biological consequences of CD45 association with the T cell receptor. Increased understanding of the role of CD45 in T cell activation has direct application to the different functional characteristics of naive, memory and effector T cell subsets as well as the changes in T cell function associated with aging. In addition basic studies on the regulation of T cell activation have broad applicability to fields of cancer pathogenesis, autoimmunity, and infectious disease.

描述（改编自研究者摘要）：T细胞的结扎

项目成果

CD4-dependent signaling is required for a late checkpoint during Th2 development associated with resistance to activation-induced cell death.

CD4 依赖性信号传导是 Th2 发育过程中与抵抗激活诱导的细胞死亡相关的晚期检查点所必需的。

• DOI: 10.4049/jimmunol.175.9.5629
• 发表时间: 2005
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Tatari-Calderone,Zohreh;Brogdon,JenniferL;Tinsley,KevinW;Ramezani,Anahita;Leitenberg,David
• 通讯作者: Leitenberg,David

Selective regulation of TCR signaling pathways by the CD45 protein tyrosine phosphatase during thymocyte development.

• DOI: 10.4049/jimmunol.181.9.6082
• 发表时间: 2008-11-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Falahati R;Leitenberg D
• 通讯作者: Leitenberg D