Tim-3-expressing [CD4.sup.+] and [CD8.sup.+] T cells in human tuberculosis exhibit polarized effector memory phenotypes and stronger anti-TB effector functions

T-cell immune responses modulated by T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) during Mycobacterium tuberculosis (Mtb) infection in humans remain poorly understood. Here, we found that active TB patients exhibited increases in numbers of Tim-3-expressing [CD4.sup.+] and [CD8.sup.+] T cells, which preferentially displayed polarized effector memory phenotypes. Consistent with effector phenotypes, Tim-[3.sup.+] [CD4.sup.+] and Tim-[3.sup.+] [CD8.sup.+] T-cell subsets showed greater effector functions for producing Th1/Th22 cytokines and CTL effector molecules than Tim-[3.sup.-] counterparts, and Tim-3-expressing T cells more apparently limited intracellular Mtb replication in macrophages. The increased effector functions for Tim-3-expressing T cells consisted with cellular activation signaling as Tim-[3.sup.+] [CD4.sup.+] and Tim-[3.sup.+] [CD8.sup.+] T-cell subsets expressed much higher levels of phosphorylated signaling molecules p38, stat3, stat5, and Erk1/2 than Tim-3- controls. Mechanistic experiments showed that siRNA silencing of Tim-3 or soluble Tim-3 treatment interfering with membrane Tim-3-ligand interaction reduced de novo production of IFN-γ and TNF-α by Tim-3-expressing T cells. Furthermore, stimulation of Tim-3 signaling pathways by antibody cross-linking of membrane Tim-3 augmented effector function of IFN-γ production by [CD4.sup.+] and [CD8.sup.+] T cells, suggesting that Tim-3 signaling helped to drive stronger effector functions in active TB patients. This study therefore uncovered a previously unknown mechanism for T-cell immune responses regulated by Tim-3, and findings may have implications for potential immune intervention in TB.