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Signal Transduction and Targeted Therapy Oct 2020
Review
Topics: Animals; Antigens, Differentiation; Humans; Membrane Glycoproteins; Receptors, Immunologic; Tumor-Associated Macrophages
PubMed: 33037186
DOI: 10.1038/s41392-020-00356-8 -
Cells Dec 2020Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8... (Review)
Review
Siglecs (sialic acid-binding immunoglobulin-like lectins) are single-pass cell surface receptors that have inhibitory activities on immune cells. Among these, Siglec-8 is a CD33-related family member selectively expressed on human mast cells and eosinophils, and at low levels on basophils. These cells can participate in inflammatory responses by releasing mediators that attract or activate other cells, contributing to the pathogenesis of allergic and non-allergic diseases. Since its discovery in 2000, initial in vitro studies have found that the engagement of Siglec-8 with a monoclonal antibody or with selective polyvalent sialoglycan ligands induced the cell death of eosinophils and inhibited mast cell degranulation. Anti-Siglec-8 antibody administration in vivo to humanized and transgenic mice selectively expressing Siglec-8 on mouse eosinophils and mast cells confirmed the in vitro findings, and identified additional anti-inflammatory effects. AK002 (lirentelimab) is a humanized non-fucosylated IgG1 antibody against Siglec-8 in clinical development for mast cell- and eosinophil-mediated diseases. AK002 administration has safely demonstrated the inhibition of mast cell activity and the depletion of eosinophils in several phase 1 and phase 2 trials. This article reviews the discovery and functions of Siglec-8, and strategies for its therapeutic targeting for the treatment of eosinophil- and mast cell-associated diseases.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Clinical Trials as Topic; Eosinophils; Humans; Hypersensitivity; Inflammation; Lectins; Mast Cells; Mice; Mice, Transgenic
PubMed: 33374255
DOI: 10.3390/cells10010019 -
Blood Oct 2014In this issue of Blood, Iqbal et al created a novel mouse model with a strong expression of green fluorescence protein (GFP) in monocytes, tissue resident macrophages,...
In this issue of Blood, Iqbal et al created a novel mouse model with a strong expression of green fluorescence protein (GFP) in monocytes, tissue resident macrophages, and inflammatory macrophages, and may provide an important tool for future studies focusing on macrophage biology. Several transgenic mice with expression of fluorescent proteins in myeloid cells exist, among them the CCR2-RFP and the CX3CR1GFP mouse. However, both of these mice have several limitations: they are knock-in constructs under control of chemokine receptors with potential effects on monocyte mobilization from the bone marrow, recruitment to sites of inflammation, or survival. Alteration of chemokine receptor expression during macrophage differentiation may affect expression of fluorescent proteins and thus render macrophages nonfluorescent.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Differentiation; Green Fluorescent Proteins; Humans; Macrophages, Peritoneal; Monocytes; Promoter Regions, Genetic
PubMed: 25301333
DOI: 10.1182/blood-2014-07-590372 -
Immunological Reviews Mar 2017Many Siglecs function as inhibitory receptors on innate and adaptive immune cells and may contribute to the attenuation of immune responses to tumors. Siglec 9 on... (Review)
Review
Many Siglecs function as inhibitory receptors on innate and adaptive immune cells and may contribute to the attenuation of immune responses to tumors. Siglec 9 on neutrophils and Siglec 7 on NK cells are prominent examples of inhibitory Siglecs that can potentially dampen anti-tumor immunity. CD169 is a Siglec that may function as an adhesion molecule and a facilitator of the recognition and internalization of sialic acid decorated apoptotic bodies and exosomes derived from tumors. It can potentially contribute to both the attenuation as well as the facilitation of anti-tumor immunity. Siglecs have been best studied in the tumor context in animal models of cancer. Modulators of Siglec function are likely to be developed and investigated clinically in a cancer context over the next few years.
Topics: Adaptive Immunity; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Humans; Immunity, Innate; Immunomodulation; Immunotherapy; Killer Cells, Natural; Lectins; Neoplasms; Neutrophils; Sialic Acid Binding Ig-like Lectin 1; Sialic Acid Binding Immunoglobulin-like Lectins; Tumor Escape
PubMed: 28258691
DOI: 10.1111/imr.12526 -
The Journal of Experimental Medicine Jul 2023CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and CD86 to control adaptive immune responses. While the role of CTLA4 in restraining...
CD28 and CTLA4 are T cell coreceptors that competitively engage B7 ligands CD80 and CD86 to control adaptive immune responses. While the role of CTLA4 in restraining CD28 costimulatory signaling is well-established, the mechanism has remained unclear. Here, we report that human T cells acquire antigen-presenting-cell (APC)-derived B7 ligands and major histocompatibility complex (MHC) via trogocytosis through CD28:B7 binding. Acquired MHC and B7 enabled T cells to autostimulate, and this process was limited cell-intrinsically by CTLA4, which depletes B7 ligands trogocytosed or endogenously expressed by T cells through cis-endocytosis. Extending this model to the previously proposed extrinsic function of CTLA4 in human regulatory T cells (Treg), we show that blockade of either CD28 or CTLA4 attenuates Treg-mediated depletion of APC B7, indicating that trogocytosis and CTLA4-mediated cis-endocytosis work together to deplete B7 from APCs. Our study establishes CTLA4 as a cell-intrinsic molecular sink that limits B7 availability on the surface of T cells, with implications for CTLA4-targeted therapy.
Topics: Humans; CTLA-4 Antigen; CD28 Antigens; Antigens, CD; Ligands; Antigens, Differentiation; Abatacept; B7-2 Antigen; Membrane Glycoproteins; Immunoconjugates; B7-1 Antigen; Cell Adhesion Molecules
PubMed: 37042938
DOI: 10.1084/jem.20221391 -
Cells Dec 2020CD5 and CD6 are closely related signal-transducing class I scavenger receptors mainly expressed on lymphocytes. Both receptors are involved in the modulation of the... (Review)
Review
CD5 and CD6 are closely related signal-transducing class I scavenger receptors mainly expressed on lymphocytes. Both receptors are involved in the modulation of the activation and differentiation cell processes triggered by clonotypic antigen-specific receptors present on T and B cells (TCR and BCR, respectively). To serve such a relevant immunomodulatory function, the extracellular region of CD5 and CD6 interacts with soluble and/or cell-bound endogenous counterreceptors but also microbial-associated molecular patterns (MAMPs). Evidence from genetically-modified mouse models indicates that the absence or blockade of CD5- and CD6-mediated signals results in dysregulated immune responses, which may be deleterious or advantageous in some pathological conditions, such as infection, cancer or autoimmunity. Bench to bedside translation from transgenic data is constrained by ethical concerns which can be overcome by exogenous administration of soluble proteins acting as decoy receptors and leading to transient "functional knockdown". This review gathers information currently available on the therapeutic efficacy of soluble CD5 and CD6 receptor infusion in different experimental models of disease. The existing proof-of-concept warrants the interest of soluble CD5 and CD6 as safe and efficient immunotherapeutic agents in diverse and relevant pathological conditions.
Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; B-Lymphocytes; CD5 Antigens; Humans; Immunotherapy; Receptors, Scavenger; T-Lymphocytes
PubMed: 33287301
DOI: 10.3390/cells9122589 -
Glycobiology Jun 2016As a physician-scientist, I have pursued research related to translational immunology with the goal of improving our ability to diagnose and treat allergic, immunologic... (Review)
Review
As a physician-scientist, I have pursued research related to translational immunology with the goal of improving our ability to diagnose and treat allergic, immunologic and other diseases involving eosinophils, basophils and mast cells. We have tried to delineate novel mechanisms of human disease, working whenever possible with primary human cells and tissues, attempting to identify targets that might be amenable to the development of new therapies. As a general strategy, we have compared eosinophils, basophils, mast cells and neutrophils to look for pathways in inflammation that were unique to distinct subsets of these cells. In doing so, the concepts of glycobiology did not enter my mind until we began noticing some intriguing functional differences involving selectins and their ligands among these cell types. One simple observation, that neutrophils were coated with a glycan that allowed them to interact with an endothelial adhesion molecule while eosinophils lacked this structure, pried open the glyco-door for me. Fruitful collaborations with card-carrying glycobiologists soon followed that have forever positively influenced our science, and have enhanced our hypotheses, experimental design, research opportunities and discoveries. Within a few years, we helped to discover Siglec-8, an I-type lectin expressed only on human eosinophils, basophils, mast cells. This receptor, together with its closest mouse counterpart Siglec-F, has been the primary focus of our work now for over a decade. If not for those in the fields of glycobiology and glycoimmunology, my lab would not have made much progress toward the goal of leveraging Siglec-8 for therapeutic purposes.
Topics: Animals; Anti-Allergic Agents; Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Antigens, Differentiation, Myelomonocytic; Basophils; Eosinophils; Gene Expression Regulation; Glycomics; Humans; Hypersensitivity; Inflammation; Lectins; Ligands; Mast Cells; Mice; Molecular Targeted Therapy; Neutrophils; Polysaccharides; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 26911285
DOI: 10.1093/glycob/cww024 -
Journal of Immunology (Baltimore, Md. :... Dec 2015Cancer immunotherapy is a rapidly evolving field that exploits T cell responses to tumor-associated Ags to induce tumor rejection. Molecular identification of tumor... (Review)
Review
Cancer immunotherapy is a rapidly evolving field that exploits T cell responses to tumor-associated Ags to induce tumor rejection. Molecular identification of tumor rejection Ags has helped define several classes of Ags, including tissue differentiation and tumor germline Ags. The ability to genetically engineer Ag-specific receptors into T cells provides an opportunity to translate these findings into therapies. New immunotherapy agents, notably checkpoint inhibitors, have demonstrated unprecedented efficacy in certain cancers. However, the nature of the Ags driving those beneficial immune responses remains unclear. New evidence suggests that tumors express immunogenic, tumor-specific epitopes generated from the same mutations that drive cancer development. Correlations between cancer types responding to immunotherapies and the frequency of somatic mutations may clarify what drives natural antitumor immune responses. This fusion of tumor immunology and genetics is leading to new ways to target this class of ideal tumor-specific Ags and could allow the application of immunotherapy to many cancers.
Topics: Adoptive Transfer; Antigens, Differentiation; Antigens, Neoplasm; Epitopes, T-Lymphocyte; Humans; Neoplasms; Receptors, Antigen, T-Cell; T-Lymphocytes
PubMed: 26589749
DOI: 10.4049/jimmunol.1501657 -
International Journal of Molecular... Jan 2024The CD28 family receptors include the CD28, ICOS (inducible co-stimulator), CTLA-4 (cytotoxic T-lymphocyte antigen-4), PD-1 (programmed cell death protein 1), and BTLA... (Review)
Review
The CD28 family receptors include the CD28, ICOS (inducible co-stimulator), CTLA-4 (cytotoxic T-lymphocyte antigen-4), PD-1 (programmed cell death protein 1), and BTLA (B- and T-lymphocyte attenuator) molecules. They characterize a group of molecules similar to immunoglobulins that control the immune response through modulating T-cell activity. Among the family members, CD28 and ICOS act as enhancers of T-cell activity, while three others-BTLA, CTLA-4, and PD-1-function as suppressors. The receptors of the CD28 family interact with the B7 family of ligands. The cooperation between these molecules is essential for controlling the course of the adaptive response, but it also significantly impacts the development of immune-related diseases. This review introduces the reader to the molecular basis of the functioning of CD28 family receptors and their impact on T-cell activity.
Topics: CD28 Antigens; CTLA-4 Antigen; T-Lymphocytes; Programmed Cell Death 1 Receptor; Antigens, CD; Immunity; Immunomodulation; Antigens, Differentiation, T-Lymphocyte; Lymphocyte Activation
PubMed: 38279272
DOI: 10.3390/ijms25021274 -
British Journal of Pharmacology Nov 2017The immune system provides a large variety of immune checkpoint proteins, which involve both costimulatory and inhibitory proteins. Costimulatory proteins can promote... (Review)
Review
UNLABELLED
The immune system provides a large variety of immune checkpoint proteins, which involve both costimulatory and inhibitory proteins. Costimulatory proteins can promote cell survival, cell cycle progression and differentiation to effector and memory cells, whereas inhibitory proteins terminate these processes to halt ongoing inflammation. Immune checkpoint proteins play a pivotal role in atherosclerosis by regulating the activation and proliferation of various immune and non-immune cells, such as T-cells, macrophages and platelets. Upon activation within the atherosclerotic lesions or in secondary lymphoid organs, these cells produce large amounts of pro-atherogenic cytokines that contribute to the growth and destabilization of lesions, which can result in rupture of the lesion causing acute coronary syndromes, such as a myocardial infarction. Given the presence and regulatory capacity of immune checkpoint proteins in the circulation and atherosclerotic lesions of cardiovascular patients, modulation of these proteins by, for example, the use of monoclonal antibodies, offers unique opportunities to regulate pro-inflammatory immune responses in atherosclerosis. In this review, we highlight the latest advances on the role of immune checkpoint proteins, such as OX40-OX40L, CTLA-4 and TIM proteins, in atherosclerosis and discuss their therapeutic potential as promising immunotherapies to treat or prevent cardiovascular disease.
LINKED ARTICLES
This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Atherosclerosis; Humans; Membrane Proteins
PubMed: 28369782
DOI: 10.1111/bph.13802