Regulation of CD8+ T cell immunity to tuberculosis (pending title)

描述(申请人提供)：持续的艾滋病毒/艾滋病流行和耐多药结核分枝杆菌(Mtb)的传播使结核病在世界各地的人口中持续流行。虽然卡介苗被普遍用作疫苗，但它在预防肺结核方面并不有效。为了抗击这一持续的世界性祸害，开发结核病疫苗是当务之急。有令人信服的实验证据表明，CD8+T细胞是小鼠和其他实验动物对结核病的最佳免疫力所必需的。T细胞如何介导保护尚不完全清楚，干扰素-g是T细胞效应器功能的“终极”和“全部”的旧范例正在被打破。重要的是，有一个巨大的、临床上重要的悖论--即T细胞对结核病的免疫至关重要，但保护的一个媒介-干扰素-g并不能预测或与疾病的保护相关联。因此，一定有其他相关的保护因素。创新：我们有四个回溯基因(Rg)小鼠品系，每个品系都表达不同的TCR，识别免疫优势表位TB104-11。有趣的是，这些不同的TCR在亲和力和介导对毒力结核杆菌的保护方面存在差异。这些RG制定了可行的实验策略，以确定CD8+T细胞如何介导保护的分子基础。目的：概述：虽然CD8+T细胞在预防结核病中做出了重要贡献是毋庸置疑的，但抑制结核杆菌生长的效应功能(S)在很大程度上还不清楚。在目标1中，我们将确定在结核分枝杆菌感染过程中CD8+T细胞介导的保护作用的不同效应分子。目标2将专注于导致T细胞激活的基本信号，并确定它们如何影响保护性效应器功能的表达。这些包括1)TCR信号的强度；2)CD4+T细胞帮助和IL-2的作用；3)炎症信号3。我们对T细胞对结核分枝杆菌免疫的大部分了解来自于对原发感染的研究。为了开发疫苗，需要更全面地了解记忆T细胞反应。我们观察到重试后记忆T细胞的丢失。因此，一个重要的问题是疫苗诱导的T细胞是否具有持久的表型而不会回复到无效的T细胞。因此，在目标3中，我们将解决初级和次级CD8+T细胞反应是否在所利用的效应器途径以及它们如何被调节方面的不同。摘要：结核分枝杆菌是一种成功的病原体，尽管有强大的免疫反应，但仍在人类体内持续存在。我们有三个目标：1)确定CD8+T细胞用来限制细菌复制的机制；2)确定效应机制是如何调节的；3)确定初级和次级CD8+T细胞的反应是否受到不同的调节。我们的答案不仅将阐明T细胞如何介导保护，而且我们希望验证可以作为生物标志物来指导疫苗开发和评估的保护途径。

DESCRIPTION (provided by applicant): The continuing HIV/AIDS epidemic and the spread of multi-drug resistant Mycobacterium tuberculosis (Mtb) has perpetuated an epidemic of tuberculosis in populations around the world. While BCG is used universally as a vaccine, it is not effective in preventing pulmonary tuberculosis. To combat this ongoing worldwide scourge, vaccine development for tuberculosis is a priority. Convincing experimental evidence exists that CD8+ T cells are required for optimal immunity to tuberculosis in mice and other experimental animals. How T cell mediate protection is incompletely understood, and the old paradigm that IFN-g is "end-all" and "be- all" of T cell effector function is being dismantled. Importantly, ther is a huge, clinically important paradox - namely that T cells are crucial to immunity against TB, but the one mediator of protection, IFN-g, does not predict or correlate with protection against disease. Therefore, there must be other correlates of protection. Innovation: We have four retrogenic (Rg) mouse lines, each expressing a different TCR that recognizes the immunodominant epitope TB104-11. Interestingly, these different TCRs vary in their affinity and potential to mediate protection against virulent Mtb. These Rg make feasible experimental strategies to define the molecular basis for how CD8+ T cells mediate protection. Aims: Overview: While there is little doubt that CD8+ T cells make an important contribution to protection against TB, the effector function(s) that inhibit Mtb growth are largely unknown. In Aim 1, we will determine the different effector molecules that contribute to the protection mediated by CD8+ T cells during Mtb infection. Aim 2 will focus on the basic signals that lead to T cell activation and determine how they impact the expression of protective effector functions. These include 1) strength of TCR signaling; 2) the role of CD4+ T cell help and IL-2; and 3) the inflammatory Signal 3. Much of what we know about T cell immunity to Mtb is from studies of primary infection. A more comprehensive understanding of memory T cell responses is needed for vaccine development. We observe a loss of the memory T cells following rechallenge. Thus, an important question is whether vaccine-elicited T cells have a durable phenotype without reversion to ineffectual T cells. Therefore, in Aim 3 we will address whether the primary and secondary CD8+ T cell responses differ in the effector pathways utilized and how they are regulated. Summary: Mtb is a successful pathogen that persists in humans despite a robust immune response. We have three goals: 1) define the mechanisms used by CD8+ T cells to restrict bacterial replication; 2) determine how effector mechanisms are regulated; and 3) determine whether primary and secondary CD8+ T cell responses are regulated differently. Our answers will not only illuminate how T cells mediate protection, but we expect to validate protective pathways that can function as biomarkers to guide vaccines development and evaluation.