Grant: Discovery Grants Program - Individual

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.