Tim-3 Induces Th2-Biased Immunity and Alternative Macrophage Activation during Schistosoma japonicum Infection

Abstract

bT cell immunoglobulin-and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected with Schistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response against S. japonicum infection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4 ؉ and CD8 ؉ T cells, NK1.1 ؉ cells, and CD11b؉ cells from the livers of S. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8؉ T cells or CD11b Schistosomiasis is a human helminth infection that is estimated to afflict 200 million people worldwide (1). The pathogenesis of schistosomiasis is caused by egg-induced granuloma formation and subsequent fibrosis in hepatic and intestinal tissues, which is believed to be caused by the acquisition and accumulation of immune cells in the affected organs. The immune response that occurs during this process is complicated and poorly understood. During the early stages of infection, a type 1 T-helper-cell (Th1) response is induced by parasite migration and adult worms. As the eggs are released from the mature adult worms, the response is then polarized into a Th2 response 4 to 6 weeks after the initial infection. This is then followed by the development of granulomas around the eggs trapped in the liver. Macrophages surround the deposited eggs and play a pivotal role in the formation of fibrosis (2), since these cells are involved in Th2 development during schistosomiasis (3) and undergo either M1 or M2 activation (4-6). M2 macrophages are essential for host protection via the production of interleukin-10 (IL-10) but simultaneously promote progressive pathology due to granuloma formation (7,8). Although the pathogenesis of schistosomal infection has long been known, the molecules and cells involved in immune triggering against the parasite remain enigmatic.T cell immunoglobulin-and mucin-domain-containing molecule 3 (Tim-3) is an important regulatory factor in both adaptive and innate immunity (9). Tim-3 is preferentially expressed on activated Th1 cells but not Th2 cells (10). After binding to its ligand galectin-9, Tim-3 induces the death of Th1 cells and negatively regulates the Th1 response (11-13). This process plays critical roles in autoimmunity, allergy, viral infection, and transplant tolerance (9). Increased Tim-3 also leads to CD8 ϩ T cell exhaustion, thereby abrogating proliferation, cytotoxicity, and cytokine production during viral infection (14, 15) and acute graft-versushost disease (16). Apart from T cells, Tim-3 is also expressed on a variety of other immune cells, such as natural killer (NK) cells, monocytes, macrophages, and mast cells (17-19). Tim-3 was reported to inhibit NK cell c...

Silver nanoparticle loaded collagen/chitosan scaffolds promote wound healing via regulating fibroblast migration and macrophage activation

“…Throughout the process of wound healing, macrophages play a vital role since they have the ability to phagocytose and clear necrotic tissue, pathogenic microorganisms and foreign matter 19 . They can also secrete various cytokines and chemokines to stimulate cell proliferation and collagen deposition, promoting vascularization and granulation 20 , 21 . There are two different activation patterns of macrophages, i.e.…”

A Schistosoma japonicum Infection Promotes the Expansion of Myeloid-Derived Suppressor Cells by Activating the JAK/STAT3 Pathway

“…The underlying mechanism might involve the increase in the expression of ARG1, induction of the activity of iNOS, as well as the production of ROS (17,18). It has been reported that SEA could upregulate the expression of ARG1 in isolated CD11b + myeloid cells from S. japonicum-infected mouse spleen in vitro (31). In our study, the level of L-arginine metabolic products (ARG1, NO, and ROS) in spleen MDSCs was compared between normal and S. japonicum-infected mice.…”

Down-Regulation of Tim-3 in Monocytes and Macrophages in Plasmodium Infection and Its Association with Parasite Clearance

“…Tim-3 was reported to engage in alternative macrophage activation (Hou et al, 2015 ). Classically activated macrophages (M1 macrophages) participate in phagocytosis, secrete antimicrobial molecules, and activate adaptive immune responses; alternatively activated macrophages (M2 macrophages) participate in the resolution of inflammation after infection (Murray et al, 2014 ).…”

“…Quantitative real-time PCR was performed to analyse the expression of genes in both human and mouse immune cells. The details of the QRT-PCR assay were previously described (Hou et al, 2015 ). The primers for the genes were derived from the Primer Bank ( https://pga.mgh.harvard.edu/primerbank/ ) and are listed in Supplementary Table 2 .…”

“…Additionally, the Tim-3-galectin 9 interaction leads to macrophage activation and stimulates bactericidal activity (Jayaraman et al, 2010 ). However, Tim-3 was found to inhibit macrophage activation in murine acute Coxsackievirus B3-induced myocarditis (Frisancho-Kiss et al, 2006 ) and murine Schistosoma japonicum ( S. japonicum ) infection (Hou et al, 2015 ). Functional inhibition by Tim-3 was also detected in human peripheral blood CD14 + monocytes (Zhang et al, 2012 ).…”