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

描述（由申请人提供）：病毒特异性cd8 + T细胞通过直接消除被感染细胞和分泌一些可溶性因子在控制病毒感染中发挥核心作用。然而，尽管在慢性HIV-1感染中诱导了强烈而广泛的HIV特异性CD8+ T细胞反应，但这些细胞逐渐失去了关键的效应功能。最近的一些研究表明，CD8+ T细胞的一个重要亚群在遇到抗原后似乎上调抑制“NK细胞受体”的表达，并且表达NK细胞受体的CD8+ T细胞在慢性感染小鼠中持续存在，而在清除感染的小鼠中则不存在。这些受体包括KIR家族的成员，以及人类的c型凝集素家族（NKG2）和小鼠的Ly49家族。这些受体在CD8+ T细胞上的表达可以对肿瘤特异性和病毒特异性T细胞的功能能力产生深远的影响。最近，在慢性HIV-1感染的CD8+ T细胞离散群体中也描述了KIR和NKG2A表达水平的增加。鉴于这些受体具有深刻的抑制作用，本应用旨在更好地了解KIR和NKG2A受体表达对hiv -1特异性CD8+ T细胞功能的作用。在本应用中，我们将在HIV-1感染不同阶段的受试者CD8+ T细胞上表征KIR和NKG2受体的表达谱，以确定HIV-1感染中NK细胞受体上调的动力学，阐明NK细胞受体表达对CD8+ T细胞功能的影响，这些受体是否优先富集在hiv特异性CD8+ T细胞表面，以及这种抑制作用是否可以逆转。此外，NK细胞受体介导的CD8+ T细胞活化抑制的确切机制将在免疫突触水平和TCR信号级联水平上得到表征。因此，本应用旨在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是否可能是由于抑制性NK细胞受体的上调。这些深入的研究旨在了解KIR/NKG2A对CD8+ T细胞抑制活性的潜在机制，必将有助于基础CD8+ T细胞生物学领域的研究，并有可能发现新的靶点，以在慢性感染（如HIV）的情况下重建CD8+ T细胞免疫的有效性。

DESCRIPTION (provided by applicant): 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 HIV specific 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 application 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.