The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity
TL;DR: The data suggest that the Tim-3–galectin-9 pathway may have evolved to ensure effective termination of effector TH1 cells.
Abstract: Tim-3 is a T helper type 1 (T(H)1)-specific cell surface molecule that seems to regulate T(H)1 responses and the induction of peripheral tolerance. However, the identity of the Tim-3 ligand and the mechanism by which this ligand inhibits the function of effector T(H)1 cells remain unknown. Here we show that galectin-9 is the Tim-3 ligand. Galectin-9-induced intracellular calcium flux, aggregation and death of T(H)1 cells were Tim-3-dependent in vitro, and administration of galectin-9 in vivo resulted in selective loss of interferon-gamma-producing cells and suppression of T(H)1 autoimmunity. These data suggest that the Tim-3-galectin-9 pathway may have evolved to ensure effective termination of effector T(H)1 cells.
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TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.
10,602 citations
Cites background from "The Tim-3 ligand galectin-9 negativ..."
...TIM3, the ligand of which is galectin 9 (a galectin that is upregulated in various types of cancer, including breast cancers) inhibits T helper 1 (T H 1) cell response...
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TL;DR: The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands, so drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions.
3,097 citations
Cites background from "The Tim-3 ligand galectin-9 negativ..."
...Functionally, TIM-3 binds to galectin-9 (as well as several other ligands), as supported by data showing that administration of galectin-9 in vitro causes cell death of Th1 cells in a TIM-3dependent manner (Zhu et al., 2005)....
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...other ligands), as supported by data showing that administration of galectin-9 in vitro causes cell death of Th1 cells in a TIM-3dependent manner (Zhu et al., 2005)....
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TL;DR: The current state of understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, is reviewed, and conceptual gaps in knowledge are highlighted.
Abstract: Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge. Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069–86. ©2018 AACR.
1,893 citations
TL;DR: This guide to cancer immunotherapy provides a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation.
Abstract: The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.
1,695 citations
TL;DR: Different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, the activation of negative costimulatory signals, and the elaboration of immunosuppressive factors are discussed.
Abstract: Despite major advances in understanding the mechanisms leading to tumor immunity, a number of obstacles hinder the successful translation of mechanistic insights into effective tumor immunotherapy. Such obstacles include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, the activation of negative costimulatory signals, and the elaboration of immunosuppressive factors. In addition, we underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network; these include regulatory T cells, natural killer T cells, and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms may be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression.
1,602 citations
Cites background from "The Tim-3 ligand galectin-9 negativ..."
...Particularly interesting, Zhu and colleagues recently showed that galectin-9 can act as a ligand of Tim-3, a Th1-specific cell surface molecule and negatively regulate Th1 responses (138)....
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References
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TL;DR: Two types of cloned helper T cells are described, defined primarily by differences in the pattern of lymphokines ynthesized, and the different functions of the two types of cells and their lymphokine synthesis are discussed.
Abstract: Effector functions in the immune system are carried out by a variety of cell types, and as our understanding of the complexity of the system expands, the number of recognized subdivisions of cell types also continues to increase. B lymphocytes, producing antibody, were initially distinguished from T lymphocytes, which provide help for B cells (1, 2). The T-cell population was further divided when surface markers allowed separation of helper cells from cytotoxic cells (3). Although there were persistent reports of heterogeneity in the helper T-cell compartment (reviewed below), only relatively recently were distinct types of helper cells resolved. In this review we describe the differences between two types of cloned helper T cells, defined primarily by differences in the pattern of lymphokines ynthesized, and we also discuss the different functions of the two types of cells and their lymphokines. Patterns of lymphokine synthesis are convenient and explicit markers to describe T-cell subclass differences, and evidence increases that many of the functions of helper T cells are predicted by the functions of the lymphokines that they synthesize after activation by antigen and presenting cells. The separation of many mouse helper T-cell clones into these two distinct types is now well established, but their origin in normal T-cell populations is still not clear. Further divisions of helper T cells may have to be recognized before a complete picture of helper T-cell function can be obtained.
7,814 citations
Additional excerpts
...dtd" [ ]> In adaptive immunity CD4 + T cells differentiate into T helper 1 (T H 1) and T H 2 cells in response to different antigenic stimulatio...
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TL;DR: The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses.
Abstract: The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses. Defining the cellular and molecular mechanisms of helper-T-cell differentiation should lead to rational strategies for manipulating immune responses for prophylaxis and therapy.
4,578 citations
"The Tim-3 ligand galectin-9 negativ..." refers background in this paper
..., whereas uncontrolled T H 2 responses have been linked to allergy and atop...
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1,890 citations
"The Tim-3 ligand galectin-9 negativ..." refers background in this paper
...T H 1 cells produce interleukin 2 (IL-2) and interferon-γ (IFN-γ), elicit delayed-type hypersensitivity responses and induce cell-mediated immunity against intracellular pathogens, whereas T H 2 cells produce IL-4, IL-5, IL-10 and IL-13, mediate immunoglobulin G 1 (IgG 1 ) and IgE production and eosinophilic inflammation and promote immunity to extracellular parasite...
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TL;DR: In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages.
Abstract: Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.
1,410 citations
"The Tim-3 ligand galectin-9 negativ..." refers background in this paper
...Tim-3, a T H 1-specific type 1 membrane protein, is not expressed on the surfaces of naive T cells but emerges on the cell surface of fully differentiated T H 1 cell...
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TL;DR: A large body of evidence suggests the existence of polarized human T cell responses, reminiscent of Th1 and Th2 subsets described for mouse T cells, which appear to be involved in organ specific autoimmunity, in contact dermatitis, and in some chronic inflammatory disorders of unknown etiology.
Abstract: A large body of evidence suggests the existence of polarized human T cell responses, reminiscent of Th1 and Th2 subsets described for mouse T cells. Human Th1-like cells preferentially develop during infections by intracellular bacteria, protozoa, and viruses, whereas Th2-like cells predominate during helminthic infestations and in response to common environmental allergens. The cytokine profile of "natural immunity" evoked by different offending agents in the context of different host genetic backgrounds appears to be a critical factor in determining the phenotype of the subsequent specific response. Strongly polarized human Th1-type and Th2-type responses not only play different roles in protection, they can also promote different immunopathological reactions. Th1-type responses appear to be involved in organ specific autoimmunity, in contact dermatitis, and in some chronic inflammatory disorders of unknown etiology. In contrast, in genetically predisposed hosts, Th2-type responses against common environmental allergens are responsible for triggering of allergic atopic disorders. Altered profiles of lymphokine production may account for immune dysfunctions in some primary or acquired immunodeficiency syndromes. The role of lymphokines produced by T cells in the pathogenesis of systemic autoimmune disorders is less clear. Further work is also required to better clarify the role of T cell-derived lymphokines in protecting against tumors or in favoring their development.
1,403 citations