Abstract
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.
Highlights
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, remains a leading cause of morbidity and mortality worldwide [1]
As an initial step to characterize potential roles of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) expression in human TB, we performed ex vivo polychromatic flow cytometric analysis in 9 healthy controls (HCs), 30 subjects with latent TB infection (LTBI), and 30 untreated active TB patients (Clinical characteristics of the enrolled subjects with LTBI or active TB disease were shown in Supporting information, Table S1)
In agreement with TB-driven upregulation of Tim-3 and Gal-9 in Mtb-infected macaques [25], we found up-regulation of Tim-3 and Gal-9 and significant increases in numbers of Tim-3 or Gal-9-expressing CD4+ and CD8+ T cells in active TB patients when compared with HCs(Figure 1 and Supporting Information, Figure S1)
Summary
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, remains a leading cause of morbidity and mortality worldwide [1]. CD4+ and CD8+ T cells may be important for host immune resistance to TB in humans [2,3,4,5]. It is likely that CD4+ and CD8+ T-cell effector functions producing. Th1 or cytotoxic cytokines are required to mount anti-mycobacterial immunity [2,4,5]. In this context, insufficiency or failure to mount anti-mycobacterial effector functions by CD4+ and CD8+ T cells may lead to impaired immunity against TB [2]. It is important to elucidate functional characteristics and regulatory pathways for Mtb-specific CD4+ and CD8+ T cells during immune responses to Mtb infection
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