Tim-3-Expressing CD4+ and CD8+ T Cells in Human Tuberculosis (TB) 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+ and cd8+ t cells,which preferentially displayed polarized effector memory phenotypes. consistent with effector phenotypes,tim-3+cd4+ and tim-3+cd8+ t-cell subsets showed greater effector functions for producing th1/th22 cytokines and ctl effector molecules than tim-3- 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+cd4+ and tim-3+cd8+ 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+ and cd8+ 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. © 2012 qiu et al.