Immune function and mechanism of Tim3 expression and Tim3+ T cells in TB & HIV+TB

描述(申请人提供)：虽然T细胞在抵抗结核分枝杆菌(Mtb)感染的宿主防御中发挥作用，但过度反应的T细胞反应可能导致结核病(TB)炎症和病变。因此，重要的是要确定结核病的免疫调节和T细胞反应的功能。T细胞免疫球蛋白和粘蛋白结构域包含分子3(Tim-3)是一种膜蛋白，最初被认为是一种负调控因子。 Th1细胞。然而，新的研究表明，TIM-3在感染中的表达/功能似乎比之前认为的更加多样化。我们最近发现，在猕猴和人类中，活动性结核显著上调了TIM-3的表达，并且TIM-3+CD4+/CD8+T细胞表现出极化的效应记忆表型。与TIM-3-T细胞相比，TIM-3+CD4+/CD8+T细胞亚群在产生Th1/Th22/CTL细胞因子和抑制细胞内Mtb方面具有更强的效应功能。TIM-3+CD4+/CD8+T细胞亚群比TIM-3-对照组表达更高水平的磷酸化信号分子p38、STAT3、STAT5和ERK1/2。TIM-3途径的沉默降低了TB的T细胞效应功能，而刺激TIM-3则增强了T细胞效应功能。我们的新发现暗示了一种新的范式，即TIM-3信号促进了活动性结核病患者更强的效应器功能。我们还发现PD-1+和PD-1-T细胞表达不同的miRNA信号，而PD-1+T细胞中人miRNA miR-31的下调增强了活动性TB的效应功能。由于感染时大量的CD4+和CD8+T细胞表达Tim-3，因此确定Tim-3+CD4+/CD8+T细胞是保护性的还是有害的及其作用机制至关重要。我们推测，我们选择的miRNAs有助于控制或调节人类TB或HIV+TB中Tim-3+CD4+和CD8+T细胞的效应功能，并且Tim-3+T细胞效应细胞可能具有参与抗TB免疫和TB炎症和病变的过度反应免疫病理的双刃性功能。我们的具体目标是：目标1.确定TIM-3+T细胞中选定的miRNAs是否控制或调节活动期人类结核病患者TIM-3+CD4+/CD8+T细胞的效应功能。目的II.研究HIV-1感染中特定的miRNA信号是否可能抑制HIV+TB患者Tim-3+CD4+/CD8+T细胞的抗结核效应功能。目的III.检测慢性肺结核期间应用r-Galectin-9是否能减少或耗尽TIM-3+CD4+/CD8+T细胞，减轻免疫病理和结核病病变。目的：确定在结核分枝杆菌感染早期通过过继转移TIM-3+T细胞快速增加的TIM-3+T效应细胞是否具有免疫保护作用。

DESCRIPTION (provided by applicant): While T cells play a role in host defense against Mycobacterium tuberculosis (Mtb) infection, over-reacting T cell responses may contribute to tuberculosis (TB) inflammation and lesions. It is, therefore, important to characterize immune regulation and function of T cell responses in TB. T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) is a membrane protein initially identified as a negative regulator of Th1 cells. However, new studies suggest that Tim-3 expression/ functions in infections appear to be more diverse than previously thought. We have recently found that active TB in macaques and humans remarkably up- regulated Tim-3 expression and that Tim-3+ CD4+/CD8+ T cells displayed polarized effector memory phenotypes. Tim-3+ CD4+/CD8+ T cell subsets showed greater effector functions for producing Th1/Th22/CTL cytokines and for inhibiting intracellular Mtb than Tim-3- T cells. Tim-3+ CD4+/CD8+ T cell subsets are more activated as they expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Silencing of Tim-3 pathway reduced T cell effector function in TB, and stimulation of Tim-3 augmented T effector functions. Our novel findings implicate a new paradigm that Tim-3 signaling facilitates stronger effector functions in active TB patients. We also found that PD-1+ and PD-1- T cells expressed distinct miRNA signatures, and down-regulation of human miRNA miR-31 in PD-1+ T cells enforces stronger effector functions during active TB. Since large numbers of CD4+ and CD8+ T cells express Tim-3 in infections, it is critical to determine whether Tim-3+ CD4+/CD8+ T cells are protective or detrimental, and functional mechanisms. We hypothesize that selected miRNAs help to control or regulate effector functions of Tim-3+ CD4+ and CD8+ T cells in human TB or HIV+TB, and that Tim-3+ T cell effector cells may have double-edge function contributing to both anti-TB immunity and over-reactive immune pathology for TB inflammation and lesions. Our specific aims are: Aim I. Determine if selected miRNAs in Tim-3+ T cells control or regulate effector functions of Tim- 3+ CD4+/CD8+ T cells in active human TB. Aim II. Investigate if selected miRNA signatures in HIV-1 infection potentially depress anti-TB effector functions of Tim-3+ CD4+/CD8+ T cells in HIV+ TB. Aim III. Examine if r-galectin-9 administration during chronic TB can reduce or deplete Tim-3+ CD4+/CD8+ T cells and attenuate immunopathology and TB lesions in macaques. Aim IV. Determine if rapid increases in Tim-3+ T effector cells by adoptive transferring of Tim-3+ T cells during early Mtb infection can confer immune protection against TB in macaques.