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Cold Spring Harbor Perspectives in... May 2019Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate... (Review)
Review
Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate high-affinity IL-2R and IL-2 is used to grow activated T cells in vitro, daclizumab was envisioned to selectively inhibit activated T cells. However, the mechanism of action (MOA) of daclizumab is surprisingly broad and it includes many unanticipated effects on innate immunity. Specifically, daclizumab modulates the development of innate lymphoid cells, leading to expansion of immunoregulatory CD56 natural killer (NK) cells. Activated CD56 NK cells migrate to the intrathecal compartment in multiple sclerosis (MS) and regulate autoreactive T cells via cytotoxicity. Finally, daclizumab also restricts initial steps of T-cell activation by blocking -presentation of IL-2 by dendritic cells to antigen-specific T cells. In conclusion, daclizumab has complex immunomodulatory effects with resultant inhibition of central nervous system inflammation in MS.
Topics: Clinical Trials as Topic; Daclizumab; Humans; Immunoglobulin G; Immunosuppressive Agents; Killer Cells, Natural; Lymphocyte Activation; Multiple Sclerosis; T-Lymphocytes
PubMed: 29661806
DOI: 10.1101/cshperspect.a034470 -
Advanced Drug Delivery Reviews May 2017The once nascent field of immunoengineering has recently blossomed to include approaches to deliver and present biomolecules to program diverse populations of... (Review)
Review
The once nascent field of immunoengineering has recently blossomed to include approaches to deliver and present biomolecules to program diverse populations of lymphocytes to fight disease. Building upon improved understanding of the molecular and physical mechanics of lymphocyte activation, varied strategies for engineering surfaces to activate and deactivate T-Cells, B-Cells and natural killer cells are in preclinical and clinical development. Surfaces have been engineered at the molecular level in terms of the presence of specific biological factors, their arrangement on a surface, and their diffusivity to elicit specific lymphocyte fates. In addition, the physical and mechanical characteristics of the surface including shape, anisotropy, and rigidity of particles for lymphocyte activation have been fine-tuned. Utilizing these strategies, acellular systems have been engineered for the expansion of T-Cells and natural killer cells to clinically relevant levels for cancer therapies as well as engineered to program B-Cells to better combat infectious diseases.
Topics: Animals; Antigen Presentation; Antigens, Surface; B-Lymphocytes; Cell Engineering; Humans; Killer Cells, Natural; Lymphocyte Activation; Lymphocytes; T-Lymphocytes
PubMed: 28501510
DOI: 10.1016/j.addr.2017.05.005 -
Current Opinion in Immunology Apr 2015
Topics: Animals; Cell Differentiation; Humans; Lymphocyte Activation; Lymphocytes; Lymphopoiesis
PubMed: 25776004
DOI: 10.1016/j.coi.2015.03.003 -
Current Opinion in Immunology Aug 2021BAFF is a critical cytokine supporting the survival of mature naïve B cells, acting through the BAFFR receptor. Recent studies show that BAFF and BAFFR are also... (Review)
Review
BAFF is a critical cytokine supporting the survival of mature naïve B cells, acting through the BAFFR receptor. Recent studies show that BAFF and BAFFR are also required for the survival of memory B cells, autoimmune B cells as well as malignant chronic lymphocytic leukaemia (CLL) cells. BAFFR cooperates with other receptors, notably the B cell antigen receptor (BCR), a process which is critical for the expansion of autoimmune and CLL cells. This crosstalk may be mediated by TRAF3 which interacts with BAFFR and with CD79A, a signalling subunit of the BCR and the downstream SYK kinase, inhibiting its activity. BAFF binding to BAFFR leads to degradation of TRAF3 which may relieve inhibition of SYK activity transducing signals to pathways required for B cell survival. BAFFR activates both canonical and non-canonical NF-κB signalling and both pathways play important roles in the survival of B cells and CLL cells.
Topics: B-Cell Activating Factor; B-Cell Activation Factor Receptor; B-Lymphocytes; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Signal Transduction
PubMed: 34352467
DOI: 10.1016/j.coi.2021.06.014 -
Journal For Immunotherapy of Cancer Dec 2022B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However,...
BACKGROUND
B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood.
METHODS
We investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing.
RESULTS
Here we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells in a cell-cell contact dependent manner by consuming more oxygen via an increase in their oxidative phosphorylation (OXPHOS). Moreover, activated B cells deprived T cells of glucose and produced lactic acid through their high glycolytic activity. Activated B cells thus inhibited the mammalian target of rapamycin pathway in T cells, resulting in suppression of T-cell cytokine production and proliferation. Finally, we confirmed the presence of tumor-associated B cells with high glycolytic and OXPHOS activities in patients with melanoma, associated with poor response to immune checkpoint blockade therapy.
CONCLUSIONS
We have revealed for the first time the immunomodulatory effects of the metabolic activity of activated B cells and their possible role in suppressing antitumor T-cell responses. These findings add novel insights into immunometabolism and have important implications for cancer immunotherapy.
Topics: T-Lymphocytes; B-Lymphocytes; Immunosuppressive Agents; Sirolimus; Immunotherapy
PubMed: 36543374
DOI: 10.1136/jitc-2022-005644 -
Journal For Immunotherapy of Cancer Nov 2023γδ T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, γδ... (Review)
Review
γδ T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, γδ T cells are more abundant in epithelial tissues where many tumors develop, and have been shown to actively participate in anticancer immunity as cytotoxic cells or as "type 1" immune orchestrators. A major asset of γδ T cells for tackling advanced cancers is their independence from antigen presentation via the major histocompatibility complex, which clearly sets them apart from conventional αβ T cells. Here we discuss the main therapeutic strategies based on human γδ T cells. These include antibody-based bispecific engagers and adoptive cell therapies, either focused on the Vδ1 or Vδ2 γδ T-cell subsets, which can be expanded selectively and differentiated or engineered to maximize their antitumor functions. We review the preclinical data that supports each of the therapeutic strategies under development; and summarize the clinical trials being pursued towards establishing γδ T cell-based treatments for solid and hematological malignancies.
Topics: Humans; Receptors, Antigen, T-Cell, gamma-delta; Neoplasms; T-Lymphocyte Subsets; Intraepithelial Lymphocytes; Hematologic Neoplasms
PubMed: 38007241
DOI: 10.1136/jitc-2023-007955 -
Journal of Immunology (Baltimore, Md. :... Jan 2018Innate lymphoid cells (ILCs) are critical components of tissues in the body, providing a first line of defense against challenges to host integrity. In contrast to... (Review)
Review
Innate lymphoid cells (ILCs) are critical components of tissues in the body, providing a first line of defense against challenges to host integrity. In contrast to strictly cytokine-producing helper ILCs, resident innate lymphocyte populations with cytolytic potential have been identified in multiple tissues in both mouse and human. These cells express the transcription factor Tbet, NK cell receptors, granzymes, perforin, and death receptors, and can directly kill tumor cells. Signals in the tumor microenvironment may promote this response, including the cytokine IL-15 and stress-associated ligands for activating NK receptors. Although there is evidence that these cells are tissue and tumor resident, their lineage remains unclear. Whether they are derived from the NK or helper ILC lineages or represent a third differentiation pathway remains to be determined. A better understanding of their lineage will help clarify their regulation and function in the context of antitumor immunity.
Topics: Animals; Cytokines; Cytotoxicity, Immunologic; Humans; Immunity, Innate; Lymphocyte Activation; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Neoplasms; Tumor Microenvironment
PubMed: 29311382
DOI: 10.4049/jimmunol.1701124 -
Frontiers in Immunology 2022The immune response to an allograft activates lymphocytes with the capacity to cause rejection. Activation of CD4CD25Foxp3T regulatory cells (Treg) can down-regulate... (Review)
Review
The immune response to an allograft activates lymphocytes with the capacity to cause rejection. Activation of CD4CD25Foxp3T regulatory cells (Treg) can down-regulate allograft rejection and can induce immune tolerance to the allograft. Treg represent <10% of peripheral CD4T cells and do not markedly increase in tolerant hosts. CD4CD25Foxp3T cells include both resting and activated Treg that can be distinguished by several markers, many of which are also expressed by effector T cells. More detailed characterization of Treg to identify increased activated antigen-specific Treg may allow reduction of non-specific immunosuppression. Natural thymus derived resting Treg (tTreg) are CD4CD25Foxp3T cells and only partially inhibit alloantigen presenting cell activation of effector cells. Cytokines produced by activated effector cells activate these tTreg to more potent alloantigen-activated Treg that may promote a state of operational tolerance. Activated Treg can be distinguished by several molecules they are induced to express, or whose expression they have suppressed. These include CD45RA/RO, cytokine receptors, chemokine receptors that alter pathways of migration and transcription factors, cytokines and suppression mediating molecules. As the total Treg population does not increase in operational tolerance, it is the activated Treg which may be the most informative to monitor. Here we review the methods used to monitor peripheral Treg, the effect of immunosuppressive regimens on Treg, and correlations with clinical outcomes such as graft survival and rejection. Experimental therapies involving ex vivo Treg expansion and administration in renal transplantation are not reviewed.
Topics: T-Lymphocytes, Regulatory; Kidney Transplantation; Isoantigens; Cytokines; Forkhead Transcription Factors
PubMed: 36426347
DOI: 10.3389/fimmu.2022.1017683 -
International Journal of Sports Medicine Aug 2022Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical... (Review)
Review
Monocyte and lymphocyte subpopulations exhibit functions that vary between the anti- and pro-inflammatory spectrum, such as classic CD16- and non-classical CD16+monocytes, as well as T helper 2 lymphocytes (Th2), the Th1/Th17 lymphocytes ratio, and T regulatory lymphocytes (Treg). Metabolic disease-associated inflammation is accompanied by an imbalance in monocyte and lymphocyte phenotypes and functionality, as well as a stronger proportion of inflammatory subpopulations. These changes appear to be important for the development and progression of diseases like diabetes and cardiovascular disease. On the other hand, the regular practice of physical exercise is an important tool to restore the functionality of monocytes and lymphocytes, and to balance the subtypes ratio. However, key variables regarding exercise prescription, such as the type of exercise, intensity, and volume differentially impact on the acute and chronic immune response in individuals diagnosed with meta-inflammation diseases. Here, we discuss the impact of different physical exercise protocols, acutely and chronically, on monocytes and lymphocytes of individuals with metabolic disease-associated inflammation. In this review, we focus on the best effects of different exercise protocols to dose the "exercise pill" in different inflammatory status.
Topics: Exercise; Humans; Inflammation; Monocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory
PubMed: 34902867
DOI: 10.1055/a-1720-0369 -
Seminars in Immunopathology Jan 2017IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers.... (Review)
Review
IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and cancer progression have been recently revisited following the discovery of T9 cells. T9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, T9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human T9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of T9 cells and their possible clinical relevance for cancer immunotherapy.
Topics: Adaptive Immunity; Animals; Cytokines; Cytotoxicity, Immunologic; Gene Expression Regulation, Neoplastic; Humans; Immunity; Immunity, Innate; Immunomodulation; Interleukin-9; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Neoplasms; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer
PubMed: 27832300
DOI: 10.1007/s00281-016-0599-4