Poly-functional analyses of vaccine-induced T cell responses

描述(摘自申请者的摘要)：开发有效的艾滋病疫苗的一个重大科学挑战是确定明确的免疫保护相关因素。这项研究的一个重要组成部分是更深入地了解基于重组载体的疫苗诱导的CD4+和CD8+T细胞反应之间的相互作用。我们的初步发现表明，疫苗诱导的CD4+和CD8+T细胞反应的功能和表型在感染后都发生了显着的改变。这些修饰比通过分析1L2和/或干扰素-γ的产生和总T细胞群体的增殖能力所揭示的更加复杂。在所提出的研究中，我们假设CD8+T细胞的功能和增殖能力依赖于多功能的CD4+T细胞反应的存在。在目标1中，我们推动了我们的研究，以确定基于重组载体的疫苗诱导的CD8+T细胞反应的功能谱(定义为细胞因子产生的模式、脱颗粒能力和抑制病毒复制的能力)将如何与疫苗诱导的CD4+T细胞反应的多功能谱相关联。在目标2中，我们将确定多功能(IL2+干扰素-γ+肿瘤坏死因子-α+)疫苗诱导的CD4+T细胞反应如何支持多功能抗原特异性CD8+T细胞的增殖能力。此外，我们假设疫苗诱导的T细胞反应受自然或抗原特异性调节性CD4和/或CD8T细胞的控制，这可能选择性地影响疫苗诱导的抗原特异性CD4+和CD8+T细胞亚群的功能及其增殖能力。在目标3中，我们将提出一种假设，即在感染的急性期存在具有与疫苗方案类似的功能和增殖能力的T细胞反应，循环抗原水平在决定其功能特征方面起着主要作用。我们还将比较疫苗诱导的T细胞反应和作为慢性病毒感染模型的针对CMV的T细胞反应。这些研究将提供关于多功能疫苗诱导的T细胞反应的相互作用的新信息，以及在存在不同水平的病毒复制的情况下，在体内感染HIV-1后它们可能如何改变。总体而言，这些发现将为疫苗诱导的T细胞反应在控制艾滋病毒感染中的重要性和命运提供新的见解。

DESCRIPTION (from applicant's abstract): A major scientific challenge in the development of an effective AIDS vaccine is the identification of clear correlates of immunoprotection. An important component in this search is a more through understanding of the interaction between the recombinant vector-based vaccine-induced CD4+ and CD8+ T cells responses. Our preliminary findings suggest that both the function and the phenotype of vaccine-induced CD4+ and CD8+ T cell responses undergo significant modification following infection. These modifications are more complex than what can be revealed through analysis of 1L2 and/or IFN-gamma production and proliferative capability of the total T cell populations. In the proposed studies, we hypothesize that the functional and proliferative capacity of CD8+ T cell functions are dependent upon the presence of poly-functional CD4+ T cell responses. In Aim 1, we have powered our studies to determine how the functional profile of recombinant vector-based vaccine-induced CD8+ T cell responses (defined as the pattern of cytokine production, ability to degranulate, and capacity to suppress virus replication) will correlate with the poly-functional profile of vaccine-induced CD4+ T cell responses. In Aim 2, we will determine how the proliferative capability of poly-functional antigen-specific CD8+ T cells is supported by the presence of poly-functional (IL2+IFN-gamma+TNF-alpha+) vaccine induced CD4+ T cell responses. Moreover, we hypothesize that vaccine-induced T cell responses are under the control of natural or antigen-specific regulatory CD4 and/or CD8 T cells that could selectively influence the functional profile of vaccine-induced antigen-specific CD4+ and CD8+ T cell subsets and their proliferative capacity. In Aim 3, we will address the hypothesis that T cell responses with function and proliferative capability similar to those induced by vaccine regimens are present during the acute phase of infection and the level of circulating antigen plays a major role in determining their functional profile. We will also compare vaccine-induced T cell responses to those directed against CMV as a model of chronic viral infection. These studies will provide new information on the interaction of poly-functional vaccine-induced T cell responses, and how they could change following "in vivo" HIV-1 infection in the presence of different levels of virus replication. Overall, these findings will shed new insights on the importance and fate of vaccine-induced T cell responses in controlling HIV-infection.