Fas Regulates T Cell Development/Function in Lpr Mice

Fas 调节 Lpr 小鼠 T 细胞发育/功能

• 批准号: 7150364
• 负责人: Ralph C Budd
• 金额: $ 38万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150364
• 关键词: CD95 molecule; DNA binding protein; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; cysteine endopeptidases; genetically modified animals; human subject; laboratory mouse; lymphocyte proliferation; mitogen activated protein kinase; nuclear factor kappa beta; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Although the Ipr genotype was identified as a mutation in the death receptor gene, fas, 13 years ago, the source of the accumulating CD4+, CD8+, and unusual CD4-CD8- (CD4-8-) TCRab+ T lymphocytes remains an enigma. Autoimmune Ipr mice manifest no significant defect in thymic negative selection or peripheral T cell deletion following activation with antigenic peptides, superantigens, or infectious agents. This grant hypothesizes that the adenopathy of Ipr mice originates from unrestrained homeostatic proliferation of T cells. This is consistent with the observation that Ipr mice develop adenopathy even in an antigen-free environment. During homeostatic proliferation in RAG1-/- mice, donor Ipr T cells accumulate to much greater numbers than wild-type T cells, and give rise to CD4-8- TGRab+ cells. Since homeostatic proliferation is driven by low affinity TCR/self-MHC-peptide signals, this suggests that the function of Fas is to eliminate T cells receiving low affinity signals from self-antigens. This model also predicts that those CD8+ T cells receiving low intensity TCR signals will become CD4-8- TCRab+. The four aims are: Aim 1 will determine whether CD8+ T cells that make low avidity or low affinity TCR interactions with peptide/MHC preferentially give rise to CD4-8- TCRab+ T cells. First, TCR/MHC avidity will be decreased by transferring polyclonal CD8+ cells (wild-type, Ipr, or Bim-/-) into scid, b2m-/-scid, and TAP-/-scid mice. The second part will vary TCR/MHC affinity using Ova-responsive OT-I T cells transferred to TAP-/-RAG-/- mice expressing different Ova peptides of varying affinity for the OT-I TCR. Aim 2 approaches the same question by fixing the antigen (H-Y) and varying the TCR using anti-H-Y TCRb (H-Yb) T cells (wild-type, Ipr, or Bim-/-) and monitoring the presence of low affinity tetramer+ cells versus high affinity clonotype+ cells. Aim 3 examines how Fas can positively signal dendritic cells for effector functions that are important for homeostatic proliferation. Aim 4 tests whether homeostatic proliferation increases the frequency/functional of autoimmune T cells. Lymphopenic conditions following chemotherapy, irradiation, and HIV infection can provoke autoimmune conditions. Hence, the regulation of homeostatic proliferation is central to autoimmune mechanisms.

描述（由申请人提供）：尽管Ipr基因型在13年前被确定为死亡受体基因的突变，但积累的CD4+， CD8+和不寻常的CD4-CD8- (CD4-8-) TCRab+ T淋巴细胞的来源仍然是一个谜。自身免疫性Ipr小鼠在抗原肽、超抗原或感染性因子激活后，胸腺阴性选择或外周T细胞缺失没有明显缺陷。