REGULATION OF IL4 SECRETION BY INVARIANT T CELLS

恒定 T 细胞对 IL4 分泌的调节

• 批准号: 6632073
• 负责人: S. Brian BRIAN Wilson
• 金额: $ 26.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632073
• 关键词: CD3 molecule; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; calcium flux; clone cells; gene expression; genetic techniques; human genetic material tag; insulin dependent diabetes mellitus; interleukin 4; monozygotic twins; pathologic process; phosphatidylinositol 3 kinase; phospholipase C; protein biosynthesis; secretion

The ablation of pancreatic beta cells by autoreactive T cells seen in Type I diabetes is thought to be the result of a complex interplay between genetic and environmental factors. In human disease, incomplete concordance between identical twins suggests that factors other than genetics contribute to disease progression. (1) Recent studies of autoimmune diseases in humans and mice have demonstrated quantitative and/or qualitative defects in an unusual population of CD4+ or CD4-CD8-, NKRP1+ T cells that use an invariant TCRalpha (Valpha24JalphaQ) chain paired with a restricted repertoire of TCR Vbeta chains. (2)(3) These cells have the unique capability to secrete large amounts of interleukin-4 (IL-4) without prior IL-4 priming, and as such, are a candidate source of early IL-4 thought to be important in biasing a T cell response towards a Th2 phenotype, and away from the pro- inflammatory Th1 phenotype seen in Type 1 diabetes. The ligand recognized by these potentially regulatory T cells is CD1d. (4) The striking conservation of CD1d and the TCRs used by invariant T cells between mice and humans indicate an important function for these cells during an immune response. In a study of identical twins discordant for Type 1 diabetes we demonstrated that there were reduced numbers of invariant T cells and a striking defect in IL-4 production in clones derived from the diabetic siblings. We hypothesize that IL-4 specific changes in TCR signaling pathways occurred during the progression to Type 1 diabetes. We propose to use Valpha24JalphaQ T cell clones raised from discordant twins to compare and contrast signaling events and gene expression patterns occurring after TCR engagement in order to identify the reason(s) for the defect in IL-4 secretion seen in the diabetic twin.

自体反应性T细胞消融胰腺细胞