Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes

Zhang, Ying; Cheng, Jun; Wang, Jia M.; Xiao, Ji; Wu, Xiao Y.; Moorman, Jonathan P.; Yao, Zhi Q.

doi:10.1189/jlb.1010591

Cited by 124 publications

(102 citation statements)

References 15 publications

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“…Monney et al 5 appointed increased macrophage numbers and activation as the major cause of exacerbated EAE in mice treated with a blocking anti-Tim-3 antibody. Frisancho-Kiss et al 15 showed that anti-Tim-3 treatment during the innate response to viral infection in BALB/c mice increases macrophages and their activation in the heart, resulting in increased inflammatory heart disease, and Zhang et al 12 found that Tim-3 regulated pro-and anti-inflammatory cytokine expression in human CD14 + monocytes. Because Tim-3 signaling has previously been associated with apoptosis, we determined the percentage of apoptotic cells and necrotic core in lesions of anti-Tim-3 mice.…”

Section: Discussionmentioning

confidence: 99%

“…9 In addition, Tim-3 can induce regulatory T-cell (Treg) activity 10 and induce expansion of myeloid-derived suppressor cells, which play an important role in tumor immunology. 11 Recently, Zhang et al 12 showed that Tim-3 can also negatively regulate innate immune responses because reduced Tim-3 signaling by antibody blockade or knockdown with small interfering RNA increases the activation of monocytes.…”

Section: Tim-3 Negatively Regulates Atherosclerosis 2559mentioning

confidence: 99%

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T-Cell Immunoglobulin and Mucin Domain 3 Acts as a Negative Regulator of Atherosclerosis

Foks

Ran

Wasserman

et al. 2013

ATVB

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Objective-Atherosclerosis is a chronic autoimmune-like disease in which lipids and fibrous elements accumulate in the arterial blood vessels. T cells are present within atherosclerotic plaques, and their activation is partially dependent on costimulatory signals, which can either provide positive or negative signals that promote T-cell activation or limit T-cell responses, respectively. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a coinhibitory type 1 transmembrane protein that affects the function of several immune cells involved in atherosclerosis, such as monocytes, macrophages, effector T cells, and regulatory T cells. In the present study, we determined the role of Tim-3 in the development of atherosclerosis. Approach and Results-Western-type diet-fed low-density lipoprotein receptor-deficient (LDLr −/− ) mice were treated with an anti-Tim-3 antibody for 3 and 8 weeks. Anti-Tim-3 administration increased fatty streak formation with 66% and increased atherosclerotic plaque formation after 8 weeks with 35% in the aortic root and with 50% in the aortic arch. Furthermore, blockade of Tim-3 signaling increased percentages of circulating monocytes with 33% and lesional macrophages with 20%. In addition, anti-Tim-3 administration increased CD4 + T cells with 17%, enhanced their activation status, and reduced percentages of regulatory T cells with 18% and regulatory B cells with 37%. Conclusions-It is known that Tim-3 acts as a negative regulator of both innate and adaptive immune responses, and in the present study, we show that anti-Tim-3 treatment augments lesion development, accompanied by an increase in the number of monocytes/macrophages and CD4 Foks et al Tim-3 Negatively Regulates Atherosclerosis 2559secretion by monocytes and antigen-presenting cells 7 and enhances macrophage clearance of intracellular pathogens. 8 However, in adaptive immune responses, Tim-3 terminates interferon-γ-driven inflammation by inducing cell death of T cells after binding to its ligand galectin-9, a soluble molecule that is upregulated by interferon-γ. 9 In addition, Tim-3 can induce regulatory T-cell (Treg) activity 10 and induce expansion of myeloid-derived suppressor cells, which play an important role in tumor immunology.11 Recently, Zhang et al 12 showed that Tim-3 can also negatively regulate innate immune responses because reduced Tim-3 signaling by antibody blockade or knockdown with small interfering RNA increases the activation of monocytes.The in vivo role of Tim-3 can be investigated using antiTim-3 antibodies, which interrupt the Tim-3-galectin-9 interactions. Previously, it was shown that blocking Tim-3 with either a Tim-3 blocking antibody or a Tim-3-Ig fusion protein enhances type 1 diabetes mellitus in nonobese diabetic mice and prevents the generation of immunologic tolerance in a transplantation model by dampening the function of Tregs. 13 Furthermore, in vivo administration of a Tim-3 blocking antibody enhances inflammation and demyelination in a mouse model of EAE by increasing the number and activa...

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Section: Discussionmentioning

confidence: 99%

Section: Tim-3 Negatively Regulates Atherosclerosis 2559mentioning

confidence: 99%

T-Cell Immunoglobulin and Mucin Domain 3 Acts as a Negative Regulator of Atherosclerosis

Foks

Ran

Wasserman

et al. 2013

ATVB

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“…In addition, HBV tends to promote M2 polarization [6,7] . Several studies have reported that pathogens can induce Tim-3 overexpression in macrophages and monocytes, which may regulate the activation and cytokine production of these cells [47] . Moreover, lipopolysaccharide, a Toll-like receptor (TLR) ligand, can repress Tim-3 expression on macrophages and at least partially rescue their function, suggesting that TLRs and their downstream pathways may be involved in the regulation of Tim-3 expression [48] .…”

Section: Tim-3 and Monocytes/macrophagesmentioning

confidence: 99%

Role of Tim-3 in hepatitis B virus infection: An overview

Liu

Gao

Liang

et al. 2016

WJG

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Hepatitis B virus (HBV) infection has received increasing public attention. hBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the abovementioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of hBV-related liver disease and suggest new therapeutic methods for intervention.

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“…Tim-3 is expressed on multiple immune cells, including activated/exhausted T cells and monocytes (13,(19)(20)(21)(22)(23)(24)(25)(26). Known ligands for Tim-3 include phosphatidylserine (27), galectin-9 (28), CEACAM1 (12), and HMGB1 (29).…”

mentioning

confidence: 99%

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 ⁺ T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

Clayton

Douglas-Vail

Rahman

et al. 2015

J Virol

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Chronic HIV infection results in a loss of HIV-specific CD8؉ T cell effector function, termed "exhaustion," which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8 ؉ T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8 ؉ T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions. IMPORTANCEDespite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression. D espite significant advances in the development of highly active antiretroviral therapy (HAART) to reduce viral replication in subjects chronically infected with human immunodeficiency virus type 1 (HIV), the immune system is incapable of completely eliminating the virus. The resulting persistent antigen levels drive a process called "T cell exhaustion," whereby responding T cells undergo hierarchical loss of their effector functions, including their ability to proliferate, their cytotoxic potential, and their ability to produce cytokines (1). Coinhibitor...

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Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes

Cited by 124 publications

References 15 publications

T-Cell Immunoglobulin and Mucin Domain 3 Acts as a Negative Regulator of Atherosclerosis

T-Cell Immunoglobulin and Mucin Domain 3 Acts as a Negative Regulator of Atherosclerosis

Role of Tim-3 in hepatitis B virus infection: An overview

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 ⁺ T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

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Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes

Cited by 124 publications

References 15 publications

T-Cell Immunoglobulin and Mucin Domain 3 Acts as a Negative Regulator of Atherosclerosis

T-Cell Immunoglobulin and Mucin Domain 3 Acts as a Negative Regulator of Atherosclerosis

Role of Tim-3 in hepatitis B virus infection: An overview

Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 + T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

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Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 ⁺ T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression