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 I V. 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.
We propose this project based on our novel observations that Tim-3+ CD4+ and CD8+ T cell subpopulations play a role in immune responses/regulation and immunity against tuberculosis or other infectious diseases. The project will examine how these cells are developed and regulated in tuberculosis, and determine if they are protective or harmful in tuberculosis.
