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: 7229030
• 负责人: Ralph C Budd
• 金额: $ 36.9万
• 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/7229030
• 关键词: Adaptor Signaling Protein; Affinity; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; Avidity; Binding; CASP8 and FADD-like apoptosis regulating protein; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Death; Cells; Cessation of life; Chronic; Class; Complex; Condition; Defect; Dendritic Cells; Environment; Frequencies; Genotype; Grant; H-Y Antigen; HIV Infections; Infectious Agent; Insulin; Ligation; Link; Lymphatic Diseases; MHC Class I Genes; Modeling; Monitor; Mus; Mutation; Numbers; Ovalbumin; Ovum; Pathway interactions; Peptide Signal Sequences; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Population; Principal Investigator; Process; Production; Rattus; Receptor Gene; Regulation; Resistance; Signal Transduction; Source; Superantigens; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; TCR Activation; TNF receptor-associated factor 2; TRAF2 gene; Testing; Transgenic Mice; Transgenic Organisms; Variant; cell type; chemokine; chemotherapy; cytokine; day; irradiation; macrophage; male; programs; promoter

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fas的突变，但累积的CD 4+、CD 8+和不寻常的CD 4-CD 8-（CD 4 -8-）TCRab+ T淋巴细胞的来源仍然是一个谜。自身免疫性Ipr小鼠在用抗原肽、超抗原或感染因子激活后胸腺阴性选择或外周T细胞缺失中没有表现出显著缺陷。 这项研究假设Ipr小鼠的淋巴结病起源于T细胞的不受限制的稳态增殖。这与Ipr小鼠即使在无抗原环境中也会发生淋巴结病的观察结果一致。在RAG 1-/-小鼠的稳态增殖过程中，供体Ipr T细胞积累到比野生型T细胞大得多的数量，并产生CD 4 -8- TGRab+细胞。由于稳态增殖是由低亲和力TCR/自身MHC肽信号驱动的，这表明Fas的功能是消除从自身抗原接收低亲和力信号的T细胞。该模型还预测那些接受低强度TCR信号的CD 8 + T细胞将变成CD 4 -8- TCRab+。这四个目标是： 目的1将确定产生低亲合力或低亲和力TCR与肽/MHC相互作用的CD 8 + T细胞是否优先产生CD 4 -8- TCRab+ T细胞。首先，通过将多克隆CD 8+细胞（野生型、Ipr或Bim-/-）转移到scid、b2 m-/-scid和TAP-/-scid小鼠中来降低TCR/MHC亲合力。第二部分将使用转移至TAP-/-RAG-/-小鼠的Ova应答性OT-I T细胞改变TCR/MHC亲和力，所述TAP-/-RAG-/-小鼠表达对OT-I TCR具有不同亲和力的不同Ova肽。 目的2通过固定抗原（H-Y）并使用抗H-Y TCRb（H-Yb）T细胞（野生型、Ipr或Bim-/-）改变TCR并监测低亲和力四聚体+细胞相对于高亲和力克隆型+细胞的存在来解决相同的问题。 目的3研究Fas如何积极信号树突状细胞的效应功能，是重要的稳态增殖。 目的4测试稳态增殖是否增加自身免疫T细胞的频率/功能。 化疗、放疗和HIV感染后的淋巴细胞减少症可引起自身免疫性疾病。因此，自我平衡增殖的调节是自身免疫机制的核心。