-
Journal For Immunotherapy of Cancer Dec 2022Myeloid-derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy....
BACKGROUND
Myeloid-derived suppressor cells (MDSCs) can potently inhibit T-cell activity, promote growth and metastasis of tumor and contribute to resistance to immunotherapy. Targeting MDSCs to alleviate their protumor functions and immunosuppressive activities is intimately associated with cancer immunotherapy. Natural killer (NK) cells can engage in crosstalk with multiple myeloid cells to alter adaptive immune responses, triggering T-cell immunity. However, whether the NK-cell-MDSC interaction can modulate the T-cell immune response requires further study. Cryo-thermal therapy could induce the maturation of MDSCs by creating an acute inflammatory environment to elicit a CD4 Th1-dominant immune response, but the mechanism regulating this process remains unclear.
METHODS
NK cells were depleted and NKG2D was blocked with monoclonal antibodies in vivo. MDSCs, NK cells and T cells were assessed by flow cytometry and isolated by magnetic-activated cell sorting (MACS). MDSCs and NK cells were cocultured with T cells to determine their immunological function. The transcriptional profiles of MDSCs were measured by qRT-PCR and RNA-sequencing. Isolated NK cells and MDSCs by MACS were cocultured to study the viability and maturation of MDSCs regulated by NK cells. TIMER was used to comprehensively examine the immunological, clinical, and genomic features of tumors.
RESULTS
NK-cell activation after cryo-thermal therapy decreased MDSC accumulation and reprogrammed immunosuppressive MDSCs toward a mature phenotype to promote T cell antitumor immunity. Furthermore, we discovered that NK cells could kill MDSCs via the NKG2D-NKG2DL axis and promote MDSC maturation by interferon gamma (IFN-γ) in response to NKG2D. In addition, CD4 Th1-dominant antitumor immune response was dependent on NKG2D, which promoted the major histocompatibility complex Ⅱ pathway of MDSCs. High activated NK-cell infiltration and NKG2D level in tumors were positively correlated with better clinical outcomes.
CONCLUSIONS
Cryo-thermal therapy induces effective CD4 Th1-dominant antitumor immunity by activating NK cells to reprogram MDSCs, providing a promising therapeutic strategy for cancer immunotherapy.
Topics: Humans; Myeloid-Derived Suppressor Cells; NK Cell Lectin-Like Receptor Subfamily K; Interferon-gamma; T-Lymphocytes; Killer Cells, Natural; Lymphocyte Activation; Neoplasms
PubMed: 36521929
DOI: 10.1136/jitc-2022-005769 -
Seminars in Immunology Dec 2012The mechanistic target of rapamycin (mTOR), an evolutionally conserved serine and threonine kinase, plays a critical role in the promotion of cell growth and... (Review)
Review
The mechanistic target of rapamycin (mTOR), an evolutionally conserved serine and threonine kinase, plays a critical role in the promotion of cell growth and proliferation via integration of cellular and environmental cues. In adaptive immunity, the mTOR pathway orchestrates multiple physiological processes including the development and homeostasis of T cells under steady state, and their subsequent activation and differentiation upon antigen recognition. Associated with such fate decisions is the dynamic reprogramming of T cell metabolic pathways, as naïve, activated and memory cells are defined by distinct bioenergetic and biosynthetic activities. Emerging evidence indicates that mTOR signaling intersects with T cell metabolism at two major levels to constitute a critical control mechanism of T cell fate decisions. First, as a central environmental sensor, mTOR links immune signaling and the availability of nutrients, especially amino acids. Second, mTOR activates specific metabolic pathways in T cells such as aerobic glycolysis (also known as the "Warburg effect") in a process dependent upon the induction of transcription factors MYC and HIF1α. Understanding how mTOR interplays with T cell metabolism to dictate T cell fates and functions will provide fundamental insights into the mechanism of immune responses and the development of novel therapeutics against immune-mediated diseases. In this review, we summarize the current advances on mTOR signaling and T cell metabolism in the control of development, homeostasis, activation and differentiation of T cells.
Topics: Animals; Cell Differentiation; Humans; Immunologic Memory; Lymphocyte Activation; T-Lymphocytes; TOR Serine-Threonine Kinases; Thymus Gland
PubMed: 23375549
DOI: 10.1016/j.smim.2012.12.004 -
International Journal of Hyperthermia :... 2012Hyperthermia (HT) is a potent sensitiser for radiotherapy (RT) and chemotherapy (CT) and has been proven to modulate directly or indirectly cells of the innate and... (Review)
Review
Hyperthermia (HT) is a potent sensitiser for radiotherapy (RT) and chemotherapy (CT) and has been proven to modulate directly or indirectly cells of the innate and adaptive immune system. We will focus in this article on how anti-tumour immunity can be induced by HT. In contrast to some in vitro assays, in vivo examinations showed that natural killer cells and phagocytes like granulocytes are directly activated against the tumour by HT. Since heat also activates dendritic cells (DCs), HT should be combined with further death stimuli (RT, CT or immune therapy) to allocate tumour antigen, derived from, for example, necrotic tumour cells, for uptake by DCs. We will outline that induction of immunogenic tumour cells and direct tumour cell killing by HT in combination with other therapies contributes to immune activation against the tumour. Studies will be presented showing that non-beneficial effects of HT on immune cells are mostly timely restricted. A special focus is set on immune activation mediated by extracellular present heat shock proteins (HSPs) carrying tumour antigens and further danger signals released by dying tumour cells. Local HT treatment in addition to further stress stimuli exerts abscopal effects and might be considered as in situ tumour vaccination. An increased natural killer (NK) cell activity, lymphocyte infiltration and HSP-mediated induction of immunogenic tumour cells have been observed in patients. Treatments with the addition of HT therefore can be considered as a personalised cancer treatment approach by specifically activating the immune system against the individual unique tumour.
Topics: Adaptive Immunity; Combined Modality Therapy; Cytokines; Dendritic Cells; Heat-Shock Proteins; Humans; Hyperthermia, Induced; Immune System; Immunity, Innate; Killer Cells, Natural; Lymphocytes
PubMed: 22690925
DOI: 10.3109/02656736.2012.677933 -
Exercise Immunology Review 2022The term immunometabolism describes cellular and molecular metabolic processes that control the immune system and the associated immune responses. Acute exercise and...
BACKGROUND
The term immunometabolism describes cellular and molecular metabolic processes that control the immune system and the associated immune responses. Acute exercise and regular physical activity have a substantial influence on the metabolism and the immune system, so that both processes are closely associated and influence each other bidirectionally.
SCOPE OF REVIEW
We limit the review here to focus on metabolic phenotypes and metabolic plasticity of T cells and macrophages to describe the complex role of acute exercise stress and regular physical activity on these cell types. The metabolic and immunological consequences of the social problem of inactivity and how, conversely, an active lifestyle can break this vicious circle, are then described. Finally, these aspects are evaluated against the background of an aging society.
MAJOR CONCLUSIONS
T cells and macrophages show high sensitivity to changes in their metabolic environment, which indirectly or directly affects their central functions. Physical activity and sedentary behaviour have an important influence on metabolic status, thereby modifying immune cell phenotypes and influencing immunological plasticity. A detailed understanding of the interactions between acute and chronic physical activity, sedentary behaviour, and the metabolic status of immune cells, can help to target the dysregulated immune system of people who live in a much too inactive society.
Topics: Energy Metabolism; Exercise; Humans; Macrophages; Sedentary Behavior; T-Lymphocytes
PubMed: 35452394
DOI: No ID Found -
BMC Geriatrics Mar 2021Interaction of physical activity and overall immune profile is very complex and depends on the intensity, duration and frequency of undertaken physical activity, the...
BACKGROUND
Interaction of physical activity and overall immune profile is very complex and depends on the intensity, duration and frequency of undertaken physical activity, the exposure to cytomegalovirus (CMV) infection and the age-related changes in the immune system. Daily physical activity, which particularly influences immunity, declines dramatically with age. Therefore, the aim of the study was to explain whether physical activity sustained throughout life can attenuate or reverse immunosenescence.
METHODS
Ninety-nine older adults (60-90 years) were recruited for the study. According to the 6-min walk test (6WMT), the Åstrand-Ryhming bike test (VOmax) and Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire, the individuals were classified as physically active (n = 34) and inactive (n = 20) groups. The analysis of T lymphocytes between active vs. inactive participants was performed using eight-parameter flow cytometry.
RESULTS
Analysis of the baseline peripheral naïve and memory T lymphocytes showed a significant relationship of lifestyle exercise with the CD4/CD8 ratio. Above 50% of physically active participants demonstrated the CD4/CD8 ratio ≥ 1 or ≤ 2.5 contrary to the inactive group who showed the ratio < 1. The older adults with the result of 6WMT > 1.3 m/s and VOmax > 35 mL/kg/min had a significantly higher CD4CD45RA T lymphocyte percentage and also a higher ratio of CD4CD45RA/CD4CD45RO. Interestingly, in active older adults with IgG CMV (n = 30) the count of CD4CD45RA T lymphocytes was higher than in the inactive group with IgG CMV (n = 20).
CONCLUSION
Based on the flow cytometry analysis, we concluded that lifestyle exercise could lead to rejuvenation of the immune system by increasing the percentage of naïve T lymphocytes or by reducing the tendency of the inverse CD4/CD8 ratio.
Topics: Aged; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Exercise; Flow Cytometry; Humans; Immunosenescence; Life Style
PubMed: 33752623
DOI: 10.1186/s12877-021-02128-7 -
Exercise Immunology Review 2007Lymphocytes recirculate between the blood and lymph moving by routes that take them through various lymphoid and non-lymphoid organs in order to search for their cognate... (Review)
Review
Lymphocytes recirculate between the blood and lymph moving by routes that take them through various lymphoid and non-lymphoid organs in order to search for their cognate antigen. Naïve and effector/memory T cells provide distinct repertoires of receptors and ligands that constitute their ability to interact with the microvessels of different anatomical compartments and, consequently, have distinct patterns of migration. Lymphocyte migration from vascular to extravascular sites is a tightly controlled cascade of events, initiated by tethering and rolling interactions of lymphocytes on the endothelial surface. Local chemokines initiate in the activation of integrin adhesiveness, followed by firm arrest and endothelial transmigration. Environmental stress induces a substantial re-distribution of T-cells within lymphoid and non-lymphoid organs. A uniform response pattern seems to exist with a decrease in lymphocyte numbers in the spleen which is accompanied by an increase in lymphocytes in lung, bone marrow and Peyer's patches. The alterations of the migration properties could be partially explained by adrenergic mechanisms which influence surface expression of adhesion molecules. Furthermore exercise and environmental stress result in a decreased expression of adhesion molecules, which might be the result of a selective mobilization of cells. In conclusion, exercise stress induces a substantial re-distribution of T-cells within lymphoid and non-lymphoid organs. It can be hypothesized that these stress-induced effects on lymphocyte trafficking might enhance immune surveillance and vigilance. However, further investigations are crucially needed to gain more insights into the underlying mechanisms.
Topics: Animals; Cell Movement; Exercise; Exercise Test; Humans; Signal Transduction; T-Lymphocytes
PubMed: 18198659
DOI: No ID Found -
International Journal of... Jun 2016The purpose of this investigation was to determine the lymphocyte subset response to 30 min of moderate treadmill exercise during caffeine supplemented (6.0 mg.kg(-1))...
The purpose of this investigation was to determine the lymphocyte subset response to 30 min of moderate treadmill exercise during caffeine supplemented (6.0 mg.kg(-1)) and placebo conditions in caffeine-naïve and -familiar individuals. Seventeen individuals participated (caffeine-familiar = 8, caffeine-naïve = 9) completing two exercise bouts (caffeine supplemented and placebo control) 48 h apart in a counterbalanced and double-blinded fashion. Individuals were classified as follows: caffeine-naive <50 mg.d(-1) and caffeine-familiar >200 mg.d(-1) Whole blood samples were obtained at rest, 30 min after caffeine or placebo ingestion, immediately following exercise, and 1 h post exercise. Blood was used to analyze apoptosis (annexin V) and cellular migration (CX3CR1) responses in lymphocyte subsets (CD4+, CD8+, CD19+). Absolute changes from rest values were calculated and differences between conditions were determined through Chi-squared analysis with significance accepted at P <0.05. With regard to CD4+ and CD19+ lymphocytes, the interaction of caffeine and exercise did not affect naïve individuals to a greater extent immediately post exercise when compared to familiar, as similar apoptotic and migratory responses were observed (P >0.05). However, CD8+ lymphocyte cell death and migration responses were observed to be significantly greater at each sampling point in caffeine-familiar individuals (P <0.05). It is possible that chronic caffeine supplementation may prime CD8+ cell receptors for responsiveness to apoptosis and migration and the consequence of this form of immunosuppression in the post-exercise period should be determined.
Topics: Adult; Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Caffeine; Cell Movement; Exercise; Exercise Test; Female; Humans; Lymphocyte Count; Male; Young Adult
PubMed: 26684634
DOI: 10.1177/0394632015612795 -
International Journal of Molecular... Aug 2019Periodontal disease is characterised by a dense inflammatory infiltrate in the connective tissue. When the resolution is not achieved, the activation of T and B cells is... (Review)
Review
Periodontal disease is characterised by a dense inflammatory infiltrate in the connective tissue. When the resolution is not achieved, the activation of T and B cells is crucial in controlling chronic inflammation through constitutive cytokine secretion and modulation of osteoclastogenesis. The present narrative review aims to overview the recent findings of the importance of T and B cell subsets, as well as their cytokine expression, in the pathogenesis of the periodontal disease. T regulatory (Treg), CD8 T, and tissue-resident γδ T cells are important to the maintenance of gingival homeostasis. In inflamed gingiva, however, the secretion of IL-17 and secreted osteoclastogenic factor of activated T cells (SOFAT) by activated T cells is crucial to induce osteoclastogenesis via RANKL activation. Moreover, the capacity of mucosal-associated invariant T cells (MAIT cells) to produce cytokines, such as IFN-γ, TNF-α, and IL-17, might indicate a critical role of such cells in the disease pathogenesis. Regarding B cells, low levels of memory B cells in clinically healthy periodontium seem to be important to avoid bone loss due to the subclinical inflammation that occurs. On the other hand, they can exacerbate alveolar bone loss in a receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent manner and affect the severity of periodontitis. In conclusion, several new functions have been discovered and added to the complex knowledge about T and B cells, such as possible new functions for Tregs, the role of SOFAT, and MAIT cells, as well as B cells activating RANKL. The activation of distinct T and B cell subtypes is decisive in defining whether the inflammatory lesion will stabilise as chronic gingivitis or will progress to a tissue destructive periodontitis.
Topics: Animals; B-Lymphocytes; Cytokines; Disease Susceptibility; Homeostasis; Humans; Lymphocyte Activation; Osteogenesis; Periodontal Diseases; T-Lymphocytes
PubMed: 31416146
DOI: 10.3390/ijms20163949 -
Clinical & Developmental Immunology 2013Five years ago, we reported the identification and characterization of several regulatory T-cell epitopes (now called Tregitopes) that were discovered in the heavy and... (Review)
Review
Five years ago, we reported the identification and characterization of several regulatory T-cell epitopes (now called Tregitopes) that were discovered in the heavy and light chains of IgG (De Groot et al. Blood, 2008). When added ex vivo to human PBMCs, these Tregitopes activated regulatory T cells (Tregs), increased expression of the transcription factor FoxP3, and induced IL-10 expression in CD4(+) T cells. We have now shown that coadministration of the Tregitopes in vivo, in a number of different murine models of autoimmune disease, can suppress immune responses to antigen in an antigen-specific manner, and that this response is mediated by Tregs. In addition we have shown that, although these are generally promiscuous epitopes, the activity of individual Tregitope peptides is restricted by HLA. In this brief report, we provide an overview of the effects of Tregitopes in vivo, discuss potential applications, and suggest that Tregitopes may represent one of the "active pharmaceutical ingredients" of IVIg. Tregitope applications may include any of the autoimmune diseases that are currently treated almost exclusively with intravenous immunoglobulin G (IVIG), such as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and Multifocal Motor Neuropathy (MMN), as well as gene therapy and allergy where Tregitopes may provide a means of inducing antigen-specific tolerance.
Topics: Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Epitopes, T-Lymphocyte; Humans; Immune Tolerance; Immunoglobulins, Intravenous; Lymphocyte Activation; Peptides; T-Lymphocytes, Regulatory
PubMed: 24454476
DOI: 10.1155/2013/493138 -
Advances in Immunology 2012Lymphocytes traverse functionally discrete stages as they develop into mature B and T cells. This development is directed by cues from a variety of different cell... (Review)
Review
Lymphocytes traverse functionally discrete stages as they develop into mature B and T cells. This development is directed by cues from a variety of different cell surface receptors. To complete development, all lymphocytes must express a functional nonautoreactive heterodimeric antigen receptor. The genes that encode antigen receptor chains are assembled through the process of V(D)J recombination, a reaction that proceeds through DNA double-stranded break (DSB) intermediates. These DSBs are generated by the RAG endonuclease in G1-phase developing lymphocytes and activate ataxia-telangiectasia mutated (ATM), the kinase that orchestrates cellular DSB responses. The canonical DNA damage response includes cell cycle arrest, DNA break repair, and apoptosis of cells when DSBs are not repaired. However, recent studies have demonstrated that ATM activation in response to RAG DSBs also regulates a transcriptional program including many genes with no known function in canonical DNA damage responses. Rather, these genes have activities that would be important for lymphocyte development. Here, these findings and the broader concept that signals initiated by physiologic DNA DSBs provide cues that regulate cell type-specific processes and functions are discussed.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; Humans; Lymphocytes; Receptors, Antigen; Signal Transduction
PubMed: 23063077
DOI: 10.1016/B978-0-12-394300-2.00006-5