T-cell Immune Responses Regulated By Tim-3and The Relationship Between The Cytokines In TB

The immune responses of CD4~+and CD8~+T cells are mostcritical aspects of host defense mechanisms against Mycobacteriumtuberculosis (M.tb). In current study, we mainly examine themechanism for M.tb-specific CD4~+and CD8~+T cells immuneresponses modulated by Tim-3in human TB disease, and therelationship among the cytokines that produced by CD4~+T cells inactive TB patients.1. T-cell immune responses modulated by T-cellimmunoglobulin and mucin domain-containing molecule3(Tim-3)during Mycobacterium tuberculosis infection in humans remainpoorly understood. Here, we found that active TB patients exhibitedincreases in numbers of Tim-3-expressing CD4~+and CD8~+T cells,which preferentially displayed polarized effector memoryphenotypes. Consistent with effector phenotypes, Tim-3~+CD4~+andTim-3~+CD8~+T-cell subsets showed greater effector functions forproducing Th1/Th22cytokines and CTL effector molecules thanTim-3-counterparts, and Tim-3-expressing T cells more apparentlylimited intracellular M.tb replication in macrophages. The increasedeffector functions for Tim-3-expressing T cells consisted withcellular activation signaling as Tim-3~+CD4~+and Tim-3~+CD8~+T-cell subsets expressed much higher levels of phosphorylated signalingmolecules p38, stat3, stat5, and Erk1/2than Tim-3-controls.Mechanistic experiments showed that siRNA silencing of Tim-3orsoluble Tim-3treatment interfering with membrane Tim-3-ligandinteraction reduced de novo production of IFN-γ and TNF-ɑ byTim-3-expressing T cells. This study therefore uncovered apreviously unknown mechanism for T-cell immune responsesregulated by Tim-3, and findings may have implications for potentialimmune intervention in TB.2. We also investigated the expression of IFN-γ andIL-22-producing CD4~+T cells, the relationship between the twocytokines in human tuberculosis. We showed that IFN-γ and IL-22were induced by human mycobacterial infection. Besides, CD4~+Tcells expressing IFN-γ and IL-22were significantly elevatedfollowing PPD stimulation. In addition, IFN-γ and IL-22-expressingCD4~+T cells were distinct from each other. We also found that therewas a reciprocal relationship between IFN-γ and IL-22production.The production of IL-22was markedly enhanced in the absence ofIFN-γ, also, the expression of IFN-γ was increased when the IL-22signaling was inhibited by monoclonal anti-IL-22mAb. Furthermore,data revealed that the detectable IL-22affected the phynotype ofIFN-γ~+CD4~+T cells. IL-22induced up-regulation of CD27 expression in IFN-γ~+CD4~+T cells, which might further confirm thatIL-22had an effect on the response of IFN-γ. Thus, this workprovides a previous unknown relationship between IFN-γ and IL-22in human TB disease.