CD8+ T cell activation and effector mechanisms

在过去，CD8+T细胞(T8细胞)被认为表现出相对有限的功能，主要限于细胞毒活性。最近，更广泛的T8细胞活性已被阐明。随着对T8细胞活性谱增加的研究的积累，人们对其激活、增殖、分化、表型表达和记忆细胞发育的方式也产生了兴趣。虽然现在人们普遍认为在某些条件下T8细胞可以独立于CD4+T细胞(T4细胞)被激活，但对于这种激活的类型和水平仍然存在相当大的争议。大多数研究都孤立地检查了CTL的活性，没有确定更广泛的T8效应器功能。到目前为止，研究普遍同意，在没有T4帮助的情况下，T8CTL可以激活，但这些“无助的”T8细胞不能进展为长期记忆细胞。这一模式最近在移植模型中受到了挑战，该模型提供的证据表明，T8的激活、效应器功能或记忆不需要T4的帮助。移植模型代表：(I)大量的抗原性挑战，(Ii)极高的反应细胞前体频率和(Iii)开始时的大量炎症。在我们的实验计划中，我们使用我们的移植模型解决了一些关于T8细胞激活和效应器功能的基本问题。产生无助的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，这个实验项目的发现将阐明钙调神经磷酸酶介导的核结合事件在T4和T8细胞激活、分化和记忆发育中的作用差异的基本方面。

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.