Anergizing effect of NK cell receptor expression on HIV-specific CD8+ T cells

病毒特异性CD8+T细胞通过直接清除感染的病毒，在控制病毒感染中发挥核心作用 细胞和分泌物中含有多种可溶性因子。然而，尽管诱导了强大而广泛的HIV特异性 慢性HIV-1感染中CD8+T细胞的反应，这些细胞逐渐失去关键效应 功能。最近的一些研究表明，CD8+T细胞的一个重要亚群似乎上调了 抗原和CD8+T细胞接触后抑制“NK细胞受体”的表达 在慢性感染的小鼠中持续表达NK细胞受体，但在清除感染的小鼠中不表达。 这些受体包括KIR家族成员以及C型凝集素家族(NKG2)的成员。 人类和小鼠体内的Ly49家族。CD8+T细胞上这些受体的表达可以有一个 对肿瘤特异性和病毒特异性T细胞的功能能力都有深远的影响。最近， 在CD8+T的离散人群中，KIR和NKG2A的表达水平也被描述为增加 慢性HIV-1感染中的细胞。鉴于这些受体的深刻抑制作用，这项提议旨在 更好地了解KIR和NKG2A受体在HIV-1特异性CD8+T细胞上表达的作用 功能。在这个应用中，KIR和NKG2受体的表达谱将被表征在 HIV-1感染者不同阶段CD8+T细胞NK细胞受体的动态变化 HIV-1感染中NK细胞受体表达上调对CD8+T细胞的影响 功能，这些受体是否优先富含在HIV特异性CD8+T细胞表面， 以及这种抑制效应能否逆转。此外，NK的确切机制 细胞受体介导的抑制CD8+T细胞活化的免疫学特征 突触水平以及TCR信号级联水平。因此，此应用程序的目标是确定 在持续病毒感染期间导致CD8+T细胞活性受损的机制之一可能是 由于抑制性NK细胞受体上调所致。这些深入的研究旨在了解 KIR/NKG2A抑制CD8+T细胞活性的潜在机制将有助于 基础CD8+T细胞生物学领域，并潜在地允许识别新的靶点以重建 CD8+T细胞免疫在慢性感染环境中的有效性，如艾滋病毒。

Virus-specific-CD8+ T cells play a central role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. However despite the induction of strong and broad HIVspecific CD8+ T cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions. A number of recent studies have shown that a significant subset of CD8+ T cells appear to upregulate inhibitory "NK cell receptor" expression following encounter with antigen, and that CD8+ T cells expressing NK cell receptors persist in chronically infected mice but not in mice that clear the infection. These receptors included members of the KIR family, as well as of the C-type lectin family (NKG2) in humans and the Ly49 family in mice. The expression of these receptors on CD8+ T cells can have a profound effect on the functional capacity of both tumor-specific and virus-specific T cells. Recently, increased levels of KIR and NKG2A expression have also been described on discrete populations of CD8+ T cells in chronic HIV-1 infection. Given the profound inhibitory effect of these receptors, this proposal aims to gain a better understanding of the role of KIR and NKG2A receptor expression on HIV-1-specific CD8+ T cell function. In this application, the expression profile of both KIR and NKG2 receptors will be characterized on CD8+ T cells in subjects at different stages of HIV-1 infection to determine the kinetics of NK cell receptor upregulation in HIV-1 infection, to elucidate the impact of NK cell receptor expression on CD8+ T cell function, whether these receptors are preferentially enriched on the surface of HIV-specific CD8+ T cells, and whether this inhibitory effect can be reversed. Furthermore, the precise mechanisms accounting for NK cell receptor-mediated inhibition of CD8+ T cell activation will be characterized on the immunological synaptic level as well as the TCR signaling-cascade level. Thus this application aims to determine whether one of the mechanisms contributing to impaired CD8+ T cell activity during persistent viral infections may be due to an up-regulation of inhibitory NK cell receptors. These in depth studies geared towards understanding the underlying mechanism of KIR/NKG2A inhibitory activity on CD8+ T cells will certainly contribute to the field of basic CD8+ T cell biology and potentially allow for the identification of novel targets to reconstitute effective of CD8+ T cell immunity in the setting of chronic infections, such as HIV.