Tregs Differentially Suppress HIV-specific CD8+ T Cells

描述(由申请人提供)：CD8+T细胞是细胞内感染如艾滋病毒的免疫反应中的关键角色。然而，在慢性感染期间，HIV特异性CD8+T细胞变得耐受，因为它们不像其他非持久性病毒感染(如流感)中的病毒特异性T细胞那样有效地增殖或杀死受感染的目标。我们已经证明，受与非进展相关的HLA等位基因(HLA-B27/-B57)限制的HIV特异性T细胞对这种类型的外周耐受具有抵抗力，这可能解释了为什么罕见的HIV感染者能够免受艾滋病的侵袭。导致HIV特异性CD8+T细胞耐受的机制(S)尚不清楚，但了解它们对于进行治疗干预至关重要。调节性T细胞(Tregs)是外周免疫耐受的最佳调节因子之一。我们的初步数据显示，受HLA-B27/-B57限制的HIV特异性T细胞对Treg介导的增殖能力抑制具有抵抗力，而受其他HLA等位基因限制的HIV特异性T细胞则对Treg介导的抑制敏感。在这项提案中，我们的目标是破译Tregs是如何引起对HIV特异性T细胞的差异抑制的。在目标1中，我们将确定抵抗Treg抑制的HIV特异性CD8+T细胞是否在能够控制HIV-1的个人中是一种常见的现象。在目标2中，我们将确定Tregs在慢性感染过程中使用哪种机制(S)来抑制HIV特异性T细胞反应，以及受HLAB27/B57限制的T细胞如何能够逃脱这种抑制。这项研究可以确定为什么某些人类白细胞抗原等位基因与HIV感染者的无进展有关。此外，如果我们定义特定的T细胞如何逃脱Treg介导的抑制，这项工作可能对其他慢性病毒感染、癌症和自身免疫性疾病的治疗干预具有深远的影响。 公共卫生相关性：这项建议旨在确定(1)逃脱Treg介导的抑制的HIV特异性T细胞是否在控制HIV-1感染的个人中是一种常见现象；(2)Treg用于抑制HIV特异性T细胞功能的机制；以及(3)HIV特异性HLA-B27/57限制的T细胞如何能够逃避Treg介导的抑制。

DESCRIPTION (provided by applicant): CD8+ T cells are key players in the immune response to intracellular infections such as HIV. However, during chronic infection HIV-specific CD8+ T cells become tolerant in that they do not proliferate or kill infected targets as efficiently as virus-specific T cells from other non-persistent viral infections (e.g. influenza). We have shown that HIV-specific T cells restricted by HLA alleles associated with non-progression (HLA-B27/-B57) are resistant to this type of peripheral tolerance, which may explain why rare HIV-infected individuals are protected from progression to AIDS. The mechanism(s) leading to HIV-specific CD8+ T cell tolerance are not known but understanding them is vital to making therapeutic intervention possible. Regulatory T cells (Tregs) are one of the best-described mediators of peripheral tolerance. Our preliminary data show that HIV-specific T cells restricted by HLA-B27/-B57 are resistant to Treg-mediated suppression of proliferative capacity whereas HIV-specific T cells restricted by other HLA alleles are susceptible to Treg-mediated suppression. In this proposal we aim to decipher how Tregs are causing differential suppression of HIV-specific T cells. In Aim 1, we will determine if HIV-specific CD8+ T cells that are resistant to Treg suppression are a common phenomenon in individuals who can control HIV-1. In Aim 2, we will determine which mechanism(s) are utilized by Tregs to suppress HIV-specific T cell responses during chronic infection and how T cells restricted by HLA-B27/B57 are able to escape from this suppression. This study could define why certain HLA alleles are associated with non- progression in HIV-infected individuals. In addition, if we define how specific T cells escape from Treg- mediated suppression this work could have far-reaching implications for therapeutic intervention in other chronic viral infections, cancer and autoimmune disease. PUBLIC HEALTH RELEVANCE: This proposal aims to determine (1) whether HIV-specific T cells that escape Treg-mediated suppression are a common phenomenon in individuals who control HIV-1 infection; (2) the mechanisms utilized by Tregs to suppress HIV-specific T cell function; and (3) how HIV-specific HLA-B27/57-restricted T cells are able to escape Treg-mediated suppression.