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Nature Reviews. Immunology Nov 2016Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation.... (Review)
Review
Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.
Topics: Animals; Cell Differentiation; Cellular Senescence; Enzyme Activation; Gene Expression Regulation; Humans; Immune System; Immunity; Immunologic Deficiency Syndromes; Lymphocyte Activation; Lymphocytes; Molecular Targeted Therapy; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Subunits; Signal Transduction
PubMed: 27616589
DOI: 10.1038/nri.2016.93 -
Annual Review of Immunology Apr 2023T cells and natural killer (NK) cells have complementary roles in tumor immunity, and dual T cell and NK cell attack thus offers opportunities to deepen the impact of... (Review)
Review
T cells and natural killer (NK) cells have complementary roles in tumor immunity, and dual T cell and NK cell attack thus offers opportunities to deepen the impact of immunotherapy. Recent work has also shown that NK cells play an important role in recruiting dendritic cells to tumors and thus enhance induction of CD8 T cell responses, while IL-2 secreted by T cells activates NK cells. Targeting of immune evasion mechanisms from the activating NKG2D receptor and its MICA and MICB ligands on tumor cells offers opportunities for therapeutic intervention. Interestingly, T cells and NK cells share several important inhibitory and activating receptors that can be targeted to enhance T cell- and NK cell-mediated immunity. These inhibitory receptor-ligand systems include CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E. We also discuss emerging therapeutic strategies based on inhibitory and activating cytokines that profoundly impact the function of both lymphocyte populations within tumors.
Topics: Humans; Animals; Killer Cells, Natural; Histocompatibility Antigens Class I; CD8-Positive T-Lymphocytes; Neoplasms; Immunotherapy; Immunity, Cellular
PubMed: 36446137
DOI: 10.1146/annurev-immunol-101921-044122 -
Annual Review of Immunology Apr 2020The discovery of CD4 T cell subset-defining master transcription factors and framing of the Th1/Th2 paradigm ignited the CD4 T cell field. Advances in in vivo... (Review)
Review
The discovery of CD4 T cell subset-defining master transcription factors and framing of the Th1/Th2 paradigm ignited the CD4 T cell field. Advances in in vivo experimental systems, however, have revealed that more complex lineage-defining transcriptional networks direct CD4 T cell differentiation in the lymphoid organs and tissues. This review focuses on the layers of fate decisions that inform CD4 T cell differentiation in vivo. Cytokine production by antigen-presenting cells and other innate cells influences the CD4 T cell effector program [e.g., T helper type 1 (Th1), Th2, Th17]. Signals downstream of the T cell receptor influence whether individual clones bearing hallmarks of this effector program become T follicular helper cells, supporting development of B cells expressing specific antibody isotypes, or T effector cells, which activate microbicidal innate cells in tissues. These bifurcated, parallel axes allow CD4 T cells to augment their particular effector program and prevent disease.
Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Cell Differentiation; Cytokines; Humans; Lymphocyte Activation; Receptors, Antigen, T-Cell; T-Lymphocyte Subsets; Th1 Cells; Th2 Cells
PubMed: 32340571
DOI: 10.1146/annurev-immunol-103019-085803 -
Frontiers in Immunology 2022In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses.... (Review)
Review
In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses. Over the past three decades, our understanding of CD4 T cell differentiation has expanded and the initial paradigm of a dichotomic CD4 T cell family has been revisited to accommodate a constantly growing number of functionally distinct CD4 T helper and regulatory subpopulations. Of note, CD4 T cells with cytotoxic functions have also been described, initially in viral infections, autoimmune disorders and more recently also in cancer settings. Here, we provide an historical overview on the discovery and characterization of cytotoxic CD4 T cells, followed by a description of their mechanisms of cytotoxicity. We emphasize the relevance of these cells in disease conditions, particularly in cancer, and we provide insights on how to exploit these cells in immunotherapy.
Topics: CD4-Positive T-Lymphocytes; Lymphocyte Activation; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th2 Cells
PubMed: 35572552
DOI: 10.3389/fimmu.2022.867189 -
Journal of Applied Physiology... May 2017The notion that prolonged, intense exercise causes an "open window" of immunodepression during recovery after exercise is well accepted. Repeated exercise bouts or... (Review)
Review
The notion that prolonged, intense exercise causes an "open window" of immunodepression during recovery after exercise is well accepted. Repeated exercise bouts or intensified training without sufficient recovery may increase the risk of illness. However, except for salivary IgA, clear and consistent markers of this immunodepression remain elusive. Exercise increases circulating neutrophil and monocyte counts and reduces circulating lymphocyte count during recovery. This lymphopenia results from preferential egress of lymphocyte subtypes with potent effector functions [e.g., natural killer (NK) cells, γδ T cells, and CD8 T cells]. These lymphocytes most likely translocate to peripheral sites of potential antigen encounter (e.g., lungs and gut). This redeployment of effector lymphocytes is an integral part of the physiological stress response to exercise. Current knowledge about changes in immune function during recovery from exercise is derived from assessment at the cell population level of isolated cells ex vivo or in blood. This assessment can be biased by large changes in the distribution of immune cells between blood and peripheral tissues during and after exercise. Some evidence suggests that reduced immune cell function in vitro may coincide with changes in vivo and rates of illness after exercise, but more work is required to substantiate this notion. Among the various nutritional strategies and physical therapies that athletes use to recover from exercise, carbohydrate supplementation is the most effective for minimizing immune disturbances during exercise recovery. Sleep is an important aspect of recovery, but more research is needed to determine how sleep disruption influences the immune system of athletes.
Topics: Athletes; Exercise; Humans; Immune System; Leukocyte Count; Lymphocytes; Monocytes; Neutrophils
PubMed: 27909225
DOI: 10.1152/japplphysiol.00622.2016 -
Nature Aug 2022The lymphocyte genome is prone to many threats, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse...
The lymphocyte genome is prone to many threats, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.
Topics: B-Lymphocytes; Cell Differentiation; Cell Proliferation; Cellular Microenvironment; DNA Damage; Germinal Center; Humans; Immunologic Memory; Lymphocytes; Mutation; Neoplasms
PubMed: 35948631
DOI: 10.1038/s41586-022-05072-7 -
Nature Reviews. Immunology Nov 2018Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a... (Review)
Review
Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.
Topics: Cytokines; Humans; Immunity, Innate; Immunotherapy, Adoptive; Killer Cells, Natural; Lymphocyte Activation; Neoplasms; T-Lymphocytes, Cytotoxic
PubMed: 30209347
DOI: 10.1038/s41577-018-0061-z -
Science Translational Medicine Oct 2021Gamma delta T (γδ T) cells are among the most potent cytotoxic lymphocytes. Activating anti–butyrophilin 3A (BTN3A) antibodies prime diverse tumor cell types to be...
Gamma delta T (γδ T) cells are among the most potent cytotoxic lymphocytes. Activating anti–butyrophilin 3A (BTN3A) antibodies prime diverse tumor cell types to be killed by Vγ9Vδ2 T cells, the predominant γδ T cell subset in peripheral circulation, by mechanisms independent of tumor antigen–major histocompatibility complex (MHC) complexes. In this report, we describe the development of a humanized monoclonal antibody, ICT01, with subnanomolar affinity for the three isoforms of BTN3A. We demonstrate that ICT01-activated Vγ9Vδ2 T cells kill multiple tumor cell lines and primary tumor cells, but not normal healthy cells, in an efficient process requiring approximately 20% target occupancy. We show that ICT01 activity is dependent on BTN3A and BTN2A but independent of the phosphoantigen (pAg)–binding B30.2 domain. ICT01 delays the growth of hematologic and solid tumor xenografts and prolongs survival of NOD/SCID/IL2rγ (NSG) mice adoptively transferred with human Vγ9Vδ2 T cells. In single- and multiple-dose safety studies in cynomolgus macaques that received up to 100 mg/kg once weekly, ICT01 was well tolerated. With respect to pharmacodynamic endpoints, ICT01 selectively activated Vγ9Vδ2 T cells without affecting other BTN3A-expressing lymphocytes such as αβ T or B cells. A first-in-human, phase 1/2a, open-label, clinical study of ICT01 was thus initiated in patients with advanced-stage solid tumors (EVICTION: NCT04243499; EudraCT: 2019-003847-31). Preliminary results show that ICT01 was well tolerated and pharmacodynamically active in the first patients. Digital pathology analysis of tumor biopsies of a patient with melanoma suggests that ICT01 may promote immune cell infiltration within the tumor microenvironment.
Topics: Lymphocyte Activation; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocytes
PubMed: 34669444
DOI: 10.1126/scitranslmed.abj0835 -
Frontiers in Immunology 2023Familial hemophagocytic lymphohistiocytosis (fHLH) encompasses a group of rare inherited immune dysregulation disorders characterized by loss-of-function mutations in... (Review)
Review
Familial hemophagocytic lymphohistiocytosis (fHLH) encompasses a group of rare inherited immune dysregulation disorders characterized by loss-of-function mutations in one of several genes involved in the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. The resulting defect in cytotoxicity allows these cells to be appropriately stimulated in response to an antigenic trigger, and also impairs their ability to effectively mediate and terminate the immune response. Consequently, there is sustained lymphocyte activation, resulting in the secretion of excessive amounts of pro-inflammatory cytokines that further activate other cells of the innate and adaptive immune systems. Together, these activated cells and pro-inflammatory cytokines mediate tissue damage that leads to multi-organ failure in the absence of treatment aimed at controlling hyperinflammation. In this article, we review these mechanisms of hyperinflammation in fHLH at the cellular level, focusing primarily on studies performed in murine models of fHLH that have provided insight into how defects in the lymphocyte cytotoxicity pathway mediate rampant and sustained immune dysregulation.
Topics: Humans; Animals; Mice; Lymphohistiocytosis, Hemophagocytic; CD8-Positive T-Lymphocytes; Killer Cells, Natural; Cytotoxicity, Immunologic; Cytokines
PubMed: 36969228
DOI: 10.3389/fimmu.2023.1147603 -
Advances in Experimental Medicine and... 2020Several experimental and human studies documented the preventive and therapeutic effects of exercise on the normal physiological function of different body systems... (Review)
Review
Several experimental and human studies documented the preventive and therapeutic effects of exercise on the normal physiological function of different body systems during aging as well as various diseases. Recent studies using cellular and molecular (biochemical, proteomics, and genomics) techniques indicated that exercise modifies intracellular and extracellular signaling and pathways. In addition, in vivo or in vitro experiments, particularly, using knockout and transgenic animals, helped to mimic physiological conditions during and after exercise. According to the findings of these studies, some important signaling pathways modulated by exercise are Ca-dependent calcineurin/activated nuclear factor of activated T-cells, mammalian target of rapamycin, myostatin/Smad, and AMP-activated protein kinase regulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha. Such modulations contribute to cell adaptation and remodeling of muscle fiber type in response to exercise. Despite great improvement in this field, there are still several unanswered questions as well as unfixed issues concerning clinical trials' biases and limitations. Nevertheless, designing multicenter standard clinical trials while considering individual variability and the exercise modality and duration will improve the perspective we have on the mechanisms mediating adaptation to exercise and final outcomes.
Topics: Adaptation, Physiological; Animals; Exercise; Humans; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Signal Transduction; T-Lymphocytes
PubMed: 32342449
DOI: 10.1007/978-981-15-1792-1_3