Tim-3 Promotes Listeria monocytogenes Immune Evasion by Suppressing Major Histocompatibility Complex Class I

Abstract

Background T-cell immunoglobulin and mucin protein 3 (Tim-3) is an immune checkpoint inhibitor that has therapeutic implications for many tumors and infectious diseases. However, the mechanisms by which Tim-3 promotes immune evasion remain unclear. Methods In this study, we demonstrated that Tim-3 inhibits the expression of major histocompatibility complex class I (MHC-I) in macrophages at both the messenger ribonucleic acid and protein levels by inhibiting the STAT1-NLRC5 signaling pathway. Results As a result, MHC-I-restricted antigen presentation by macrophages was inhibited by Tim-3 both in vitro and in a Listeria monocytogenes infection model in vivo. Systemic overexpression of Tim-3 or specific knockout of Tim-3 in macrophages significantly attenuated or enhanced CD8+ T-cell activation and infection damage in L monocytogenes-infected mice, respectively. Conclusions Thus, we identified a new mechanism by which Tim-3 promotes L monocytogenes immune evasion. Further studies on this pathway might shed new light on the physio-pathological roles of Tim-3 and suggest new approaches for intervention.

T cell immunoglobulin and mucin domain protein 3 inhibits glycolysis in RAW 264.7 macrophages through Hexokinase 2

“…We previously demonstrated that Tim-3 downregulation/blockage is accompanied by inflammatory cytokine secretion, which leads to inflammatory phenotype shifting. 42 Surprisingly when we used soluble Tim-3 (sTim-3) protein to block the Tim-3/ Tim-3-ligand interactions in cultured macrophages as reported previously, 38,39 the supernatants displayed lowered pH values than those collected from control protein-treated cells, suggesting that Tim-3 signalling influences macrophage metabolism ( Figure S1). To test this hypothesis, we first ruled out the possibility of sTim-3 inducing macrophage proliferation and apoptosis, and the results showed no significant changes ( Figure S2 and S3.…”

“…Intriguingly, our previous reports and reports from other groups showed that Tim‐3 regulates different phenotypes of macrophages. Tim‐3 signal blockade leads to the inflammatory phenotype with increased expressions of TNF‐α IL‐β, NOS2, IL‐12 and CD16/32 40,56 . Upregulated Tim‐3 signal results to the anti‐inflammatory phenotype with increased expressions of IL‐10, Arg‐1 and Detectin‐1 38,57,58 .…”

“…Tim-3 signal blockade leads to the inflammatory phenotype with increased expressions of TNF-α IL-β, NOS2, IL-12 and CD16/32. 40,56 Upregulated Tim-3 signal results to the anti-inflammatory phenotype with increased expressions of IL-10, Arg-1 and Detectin-1. 38,57,58 Moreover, we previously found that Tim-3 also downregulated the activation of NLRP3, 59 which helps the host to resist pathogen invasion.…”

“…The Tim‐3‐flox/flox mice (C57BL/6) used in this study were generated at the Transgenic Core Facility of Cyagen Biosciences, Inc Myeloid cell‐specific Tim‐3 conditional knockout (Tim‐3KO) (Tim‐3fl/flLyz2cre/+) C57BL/6 mice were generated by mating Tim‐3‐flox mice with Lyz2‐cre mice. The development of Tim‐3TG and control (WT), and the Tim‐3KO mice and their control (WT) mice were described previously 38‐40 . All mice were bred and maintained under specific pathogen‐free conditions and were treated in strict compliance with the guidelines for the care and use of laboratory animals set out by the Institute of Military Cognitive and Brain Sciences.…”

“…The development of Tim-3TG and control (WT), and the Tim-3KO mice and their control (WT) mice were described previously. [38][39][40] All mice were bred and maintained under specific pathogen-free conditions and were treated in strict compliance with the guidelines for the care and use of laboratory animals set out by the Institute of Military Cognitive and Brain Sciences. The protocol was approved by the Ethics Committee of Animal Experiments of the Institute of Military Cognitive and Brain Sciences (permit number: AMMS2017-0188).…”