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

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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.