Tim-3 pathway dysregulation and targeting in sepsis-induced immunosuppression

Abstract

Sepsis is a major medical problem which causes millions of deaths worldwide every year. The host immune response in sepsis is characterized by acute inflammation and a simultaneous state of immunosuppression. In the later stage of sepsis, immunosuppression is a crucial factor that increases the susceptibility of septic patients to secondary infection and mortality. It is characterized by T cell exhaustion, excessive production of anti-inflammatory cytokines, hyperproliferation of immune suppressor cells and aberrant expression of immune checkpoint molecules. T cell immunoglobulin and mucin domain 3 (Tim-3), an immune checkpoint molecule, is found on the surface of various cells, including macrophages, NK cells, NKT cells, and T cells. There are four different ligands for Tim-3, and accumulating evidence indicates that Tim-3 and its ligands play a crucial role in regulating immune cell dysfunction during sepsis. Anti-Tim-3 antibodies have been applied in the field of cancer immunotherapy and have achieved positive therapeutic effects in some clinical trials. However, the therapeutic efficacy of Tim-3 blockade is still controversial in animal models of sepsis. These challenges highlight the need for a deeper understanding of Tim-3 signaling in sepsis. This review examines the comprehensive effect of Tim-3 signaling in the development of sepsis-induced immunosuppression and the therapeutic efficacy of Tim-3 blockade.

Keywords: Immune checkpoint; Immunosuppression; Sepsis; Tim-3.

Fig. 1

Tim-3 signaling pathway. A The ligands for Tim-3 consist of Galectin-9, HMGB-1, Ceacam-1 and PtdSer. Bat3 and Fyn both bind to the identical region on the intracellular tail of Tim-3. The natural ligands binding to Tim-3 cause Tyr263 and Tyr256 on the intracellular domain phosphorylation with subsequent Bat3 displacing and recruitment of Fyn. This triggers apoptosis in immune cells, thereby enhancing the inhibitory function of Tim-3. B α-Lactose is a disaccharide sugar that binds to Galectin-9, thereby preventing Galectin-9 from interacting with Tim-3. Anti-Tim-3 antibodies can inhibit the binding of natural ligands to Tim-3, which helps preserve the interaction between Tim-3 and Bat3. This, in turn, activates immune cells by facilitating the recruitment of Lck, restoring their functional responses

Fig. 2

The expression of Tim-3 on various immune cells and the functional alteration of these cells in sepsis-induced immunosuppression. Tim-3 is expressed by various cell types, including DC, macrophages, NK cells, NKT cell, and T cells. The expression of Tim-3 in these cells increased in sepsis-induced immunosuppression. A Tim-3 signaling in macrophages inhibits TLR4 to sense LPS to mediate NF-κB pathway by promoting PI3K-AKT and zinc finger protein A20 activation, thereby reducing cytokine production. The overexpression of Tim-3 is found to promote the polarization of M2 macrophages. B Tim-3 interacts with HMGB-1, limiting the binding of HMGB-1 to DNA, thereby inhibiting the maturation of DC cells and TLR-mediated innate immune responses; Galectin-9 binds to Tim-3 to enhance the production of IL-12 by DC cells. C The overexpression of Tim-3 leads to a reduction in the degranulation biomarker CD107a and IFN-γ production in natural killer (NK) cells. D The overexpression of Tim-3 in natural killer T (NKT) cell promotes apoptosis. On the other hand, Tim-3 can be regarded as an activation marker of NKT cell after sepsis. The expression levels of activation markers FasL and CD25/CD29 are elevated in Tim-3⁺ NKT cells, along with a notable increase in the secretion of IL-10, IL-17, and IFN-γ. E Tim-3⁺ Th1 cells demonstrate heightened expression of inhibitory markers LAG/2B4. In addition, these Tim-3⁺ Th1 cells exhibit an increased secretion of the inhibitory cytokine IL-10, while inflammatory cytokines TNF-α, IL-1β, and IFN-γ were decreased. F Tim-3 signaling in CD8⁺ T cells inhibits cell proliferation and reduces the production of the effector cytokine IFN-γ. Tim-3⁺ CD8⁺ T cells show a diminished response to antigenic stimulation. G Tim-3⁺ Tregs exhibited enhanced suppressive capacity, characterized by a significant rise in the release of inhibitory molecules such as granzyme A, perforin, and IL-10. In addition, Tim-3⁺ Tregs exhibited stronger anti-apoptotic abilities

Fig. 3

Function of dysregulated Tim-3 pathway in sepsis-induced immunosuppression. In sepsis, DCs can recognize lipopolysaccharide (LPS) through Toll-like receptors (TLRs), thereby initiating the synthesis of cytokines and promoting naive T cells differentiation and activation. However, the interaction of Galectin-9 and Tim-3 in DCs can inhibit this process. Th1 cells have the capability to secrete substantial quantities of Galectin-9 during sepsis. Thereby, Th1 can induce the development of Foxp3⁺ Tregs cells while inhibit the development of pro-inflammation IL-17 producing Th cells (Th17). The expression of Tim-3 is significantly elevated on Th17 cells, and its signaling pathway induces the death of Th17 cells while leading to a decrease in IL-17, IL-6, and TNF-α production. The activation of Tim-3 signaling on naive T cells leads to their differentiation into Treg cells. Tim-3 signaling promotes the secretion of the effector molecules IL-10, perforin, and granzyme A from Treg cells. IL-10 will decrease MHC II expression on APCs and reduce the ability of APCs to present antigen. Increased production of perforin and granzyme A leads to enhanced lysis of NK and CD8⁺ T cells. Tim-3 signaling also reduces the cytotoxicity of NK and CD8⁺ T cells. The secretion of IL-12 by DCs upon exposure to LPS significantly upregulates the expression of Tim-3 in NKT cells. In addition, Galectin-9 can synergize with LPS to enhance IL-12 production in DCs. Tim-3 serves as an activation marker of NKT cells in the early phase of sepsis. Tim-3⁺ NKT cells produced more proinflammatory cytokines and FasL and CD25/29. However, upregulation of Tim-3 also induces NKT cell apoptosis. The binding of α-Lactose to Galectin-9 hindered the production of IL-12 in DCs cells, thereby diminishing apoptosis and the expression of Tim-3 in NKT cells