Tregs Differentially Suppress HIV-specific CD8+ T Cells

描述（由申请人提供）：CD8+ T细胞在细胞内感染（如HIV）的免疫应答中起关键作用。然而，在慢性感染期间，hiv特异性CD8+ T细胞变得耐受，因为它们不像来自其他非持续性病毒感染（如流感）的病毒特异性T细胞那样有效地增殖或杀死受感染的靶标。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细胞对这种外周耐受性具有抵抗力，这可能解释了为什么罕见的hiv感染者不会进展为艾滋病。导致hiv特异性CD8+ T细胞耐受的机制尚不清楚，但了解它们对于使治疗干预成为可能至关重要。调节性T细胞（Tregs）是外周耐受性的最佳介质之一。我们的初步数据表明，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抗性，而受其他HLA等位基因限制的hiv特异性T细胞对treg介导的抑制敏感。在这个提议中，我们的目标是破译Tregs如何引起hiv特异性T细胞的差异抑制。在Aim 1中，我们将确定抵抗Treg抑制的hiv特异性CD8+ T细胞在能够控制HIV-1的个体中是否是一种常见现象。在Aim 2中，我们将确定Tregs在慢性感染期间抑制hiv特异性T细胞反应的机制，以及受HLA-B27/B57限制的T细胞如何能够摆脱这种抑制。这项研究可以确定为什么某些HLA等位基因与hiv感染者的不进展有关。此外，如果我们确定特异性T细胞如何从Treg介导的抑制中逃脱，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意义。

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.