NK cell regulation of CD4 T cell responses

对感染的免疫反应发生在两个阶段，早期相对非特异性（先天）反应和后期特异性（适应性或获得性）反应。与T细胞和B细胞抗原反应克隆扩增相关的反应。我在20世纪70年代的实验室通过展示干扰素（IFN）诱导的活化自然杀伤（NK）细胞峰值，随后是病毒特异性细胞毒性T细胞峰值，帮助发展了这一范式。NK细胞现在被认为是先天免疫系统中重要的抗病毒成分。矛盾的是，我们现在有令人惊讶的证据表明NK细胞的消耗有时可以增强病毒清除或抑制免疫病理疾病。在这些条件下，NK细胞对宿主有害，因为它们改变了获得性免疫反应，部分原因是通过杀死激活的CD4 T细胞，CD4 T细胞通过对CDS T细胞和B细胞的作用直接或间接地调节病毒感染。然而，在其他条件下，需要NK细胞的存在来促进持续感染，部分原因也是由于它们调节T细胞反应的能力。我们在这里表明，尽管抑制分子2B4抑制NK细胞攻击CDS T细胞，但活化的NK细胞可以杀死活化的CD4 T细胞，从而在病毒感染期间降低CD4和CDS T细胞的数量和功能。我们建议使用几种不同的系统来确定NK细胞影响新形成的T细胞反应和促进肺部病毒性疾病发病机制的机制，我们将与其他项目研究人员合作，将这些发现转化为人体系统。具体而言，我们提出以下具体目标：具体目标#1：确定NK细胞对T细胞反应的直接控制是否是抗病毒T细胞反应的普遍特征。特定目标#2：与Project 2和Core 0合作，确定对NK细胞介导的裂解敏感的004 T细胞的功能、生理和抗原状态。特异性目标#3：确定NK细胞在调节抗病毒抗体反应中的作用。特异性目标#4：研究NK细胞对病理和持久性的依赖调节以及NK细胞对T细胞衰竭的影响。这项工作符合RFA-AI-12-048的目标，因为它(1)研究了病毒系统中先天免疫和适应性免疫机制之间的相互作用，(2)研究了粘膜部位（在这种情况下是肺）的这种作用，(3)研究了感染后不同的T细胞和B细胞亚群是如何维持的。

Immune responses to infections occur in two phases, an early relatively nonspecitic (innate) response and a later specific (adaptive or acquired).response associated with the expansions of antigen-reactive clones of T and B cells. My laboratory in the 1970s helped develop this paradigm by demonstrating an interferon (IFN)- induced activated natural killer (NK) cell peak followed by a virus-specific cytotoxic T cell peak. NK cells are now considered important anti-viral components of the innate immune system. Paradoxically, we now have surprising evidence that the depletion of NK cells can sometimes enhance viral clearance or inhibit immunopathological disease. Under these conditions NK cells are harmful to host because they alter the acquired immune response, in part by killing activated CD4 T cells, which regulate viral infections directly and indirectly by their actions on CDS T cells and B cells. However, under other conditions the presence of NK cells is needed to promote persistent infections, also in part due to their ability to regulate T cell responses. We show here that whereas the inhibitory molecule 2B4 restrains NK cells from attacking CDS T cells, activated NK cells can kill activated CD4 T cells and in so doing decrease both CD4 and CDS T cell numbers and functionality during viral infections. We propose to determine, using several different systems, the mechanism(s) by which NK cells affect newly developing T cell responses and contribute to the pathogenesis of viral disease in the lung, and we will collaborate with, other program investigators to translate these findings into human systems. Specifically, we propose the following specific aims: Specific Aim #1: To determine whether the direct NK cell control of T cell responses is a universal feature in anti-viral T cell responses. Specific Aim #2: To determine, in collaboration with Project 2 and Core 0, the functional, physiological, and antigenic state of 004 T cells that are susceptible to NK cell mediated lysis. Specific Aim #3: To determine the role of NK cells in regulating antiviral antibody responses. Specific Aim #4: To examine the NK cell-dependent regulation of pathology and persistence and effects of NK cells on T cell exhaustion. The work meets the objectives of RFA-AI-12-048, in that it (1) examines interactions between innate and adaptive immune mechanisms in viral systems, (2) examines such actions at mucosal sites, in this case the lung, and (3) examines how different T and B cell subsets are maintained after infection.