CD8+ T cell activation and effector mechanisms

CD8 T 细胞激活和效应机制

• 批准号: 155130-2009
• 负责人: Lee, Timothy
• 金额: $ 3.64万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=475986
• 关键词: CD8+; cell; activation; effector; mechanisms

In the past, CD8+ T cells (T8 cells) have been thought to exhibit relatively limited function, primarily restricted to cytotoxic activity. Recently, a broader spectrum of T8 cell activity has been elucidated. As research has accumulated regarding the increasing spectrum of T8 cell activity, there has been a consequent interest in the manner of their activation, proliferation, differentiation, phenotype expression and memory cell development. Although it is now generally accepted that T8 cells can be activated independently of CD4+ T cells (T4 cells) under certain conditions, there remains considerable controversy over the type and level of this activation. Most studies have examined CTL activity in isolation, leaving undetermined the broader spectrum of T8 effector function. The studies to date are in general agreement that T8 CTL activation can occur in the absence of T4 help but that these "helpless" T8 cells cannot progress to long term memory cells. This paradigm has been recently challenged in a transplant model that provided evidence that T4 help was not required for T8 activation, effector function or memory. The transplant model represents: (i) a substantial antigenic challenge, (ii) extremely high responder cell precursor frequency and (iii) substantial inflammation at the outset. In our experimental program we address a number of fundamental questions regarding T8 cell activation and effector functions using our transplant model. The ablation strategy to produce "helpless" T8 cells is the introduction of therapeutic levels of CyA. We will examine a more complete spectrum of T8 activity, rather than just CTL activity. Finally, the findings of this experimental program will elucidate fundamental aspects of disparity in the role of calcineurin mediated nuclear binding events between T4 and T8 cell activation, differentiation and development of memory.

过去，人们认为CD8+ T细胞（T8细胞）的功能相对有限，主要局限于细胞毒性活性。最近，更广泛的T8细胞活性谱已被阐明。随着T8细胞活性谱的不断增加，人们对其激活、增殖、分化、表型表达和记忆细胞发育的方式产生了浓厚的兴趣。虽然目前普遍认为T8细胞在一定条件下可以独立于CD4+ T细胞（T4细胞）激活，但这种激活的类型和水平仍存在相当大的争议。大多数研究都是单独检测CTL活性，未确定T8效应物功能的更广泛范围。迄今为止的研究普遍认为，T8 CTL激活可以在没有T4帮助的情况下发生，但这些“无助的”T8细胞不能发展为长期记忆细胞。这一范式最近在移植模型中受到挑战，该模型提供的证据表明T4对T8激活、效应功能或记忆不需要帮助。移植模型代表：(i)大量的抗原挑战，（ii）极高的应答细胞前体频率和（iii）开始时的大量炎症。在我们的实验项目中，我们使用我们的移植模型解决了一些关于T8细胞激活和效应功能的基本问题。产生“无助”T8细胞的消融策略是引入治疗水平的CyA。我们将研究更完整的T8活性谱，而不仅仅是CTL活性。最后，本实验项目的发现将阐明钙调磷酸酶介导的核结合事件在T4和T8细胞活化、分化和记忆发育中的作用差异的基本方面。