MHC-independent T cells

MHC非依赖性T细胞

• 批准号: 10926134
• 负责人: Alfred Singer
• 金额: $ 70.18万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926134
• 关键词: Antibodies; Antigen Presentation; Antigens; Binding; CD8B1 gene; Cells; Detection; Goals; Ligands; Lymphocyte-Specific p56LCK Tyrosine Protein Kinase; Major Histocompatibility Complex; Malignant Neoplasms; Mus; Protein Tyrosine Kinase; Reaction; Role; Signal Transduction; Specificity; T-Lymphocyte; Testing; Thymus Gland; Transgenes; in vivo; molecular shape; prevent; receptor; thymocyte

The thymus produces MHC-restricted abT cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We hypothesized that CD4 and CD8 coreceptors might be impose MHC-specificity on a broader abTCR repertoire during thymic selection because they bind and effectively sequester the tyrosine kinase Lck, thereby preventing TCR signaling by non-MHC ligands that do not engage either coreceptor. Using mice deficient for both CD4 and CD8 as well as MHC (Quad-deficient), we discoverd that ab thymocytes can be signaled by non-MHC ligands in the absence of coreceptors in vivo. In addition, we tested the critical role of coreceptors by introducing CD4 transgenes into Quad-deficient mice. Whereas sequestration of Lck by wild-type CD4 blocked signaling by non-MHC ligands on ab thymocytes, introducing a tailless form of CD4 didnt. We conclude that in the absence of Lck sequestration by coreceptors, thymocytes can be signaled by non-MHC ligands. Therefore, CD4 and CD8 impose MHC-specificity on a broad abTCR repertoire by preventing thymocytes to be selected by non-MHC ligands.

胸腺产生MHC限制性ABT细胞，该细胞只识别与MHC或MHC样分子相关的抗原配体。我们假设，在胸腺选择过程中，CD4和CD8辅助受体可能对更广泛的abTCR谱系施加MHC特异性，因为它们结合并有效地隔离酪氨酸激酶Lck，从而阻止不与这两种辅助受体结合的非MHC配体发出TCR信号。使用缺乏CD4和CD8以及MHC(Quad缺陷)的小鼠，我们发现在体内缺乏辅助受体的情况下，AB胸腺细胞可以通过非MHC配体发出信号。此外，我们通过将CD4转基因引入Quad缺陷小鼠来测试辅助受体的关键作用。然而，野生型CD4对Lck的隔离阻止了AB胸腺细胞上非MHC配体的信号传递，引入了一种无尾形式的CD4DNT。我们的结论是，在没有LCK被辅受体隔离的情况下，胸腺细胞可以通过非MHC配体发出信号。因此，CD4和CD8通过阻止胸腺细胞被非MHC配体选择而在广泛的abTCR谱系上施加MHC特异性。