Cellular side of acquired immunity (T cells)

2013 ◽  
Author(s):  
Assia Eljaafari ◽  
Pierre Miossec
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Disease Process ◽  
T Cell Response ◽  
Th2 Cells ◽  
Cell Mediated Immunity ◽  
Immune Effector ◽  
Effector Cells ◽  
Th22 Cells

The adaptive T-cell response represents the most sophisticated component of the immune response. Foreign invaders are recognized first by cells of the innate immune system. This leads to a rapid and non-specific inflammatory response, followed by induction of the adaptive and specific immune response. Different adaptive responses can be promoted, depending on the predominant effector cells that are involved, which themselves depend on the microbial/antigen stimuli. As examples, Th1 cells contribute to cell-mediated immunity against intracellular pathogens, Th2 cells protect against parasites, and Th17 cells act against extracellular bacteria and fungi that are not cleared by Th1 and Th2 cells. Among the new subsets, Th22 cells protect against disruption of epithelial layers secondary to invading pathogens. Finally these effector subsets are regulated by regulatory T cells. These T helper subsets counteract each other to maintain the homeostasis of the immune system, but this balance can be easily disrupted, leading to chronic inflammation or autoimmune diseases. The challenge is to detect early changes in this balance, prior to its clinical expression. New molecular tools such as microarrays could be used to determine the predominant profile of the immune effector cells involved in a disease process. Such understanding should provide better therapeutic tools to counteract deregulated effector cells.

Cellular side of acquired immunity (T cells)

2013 ◽  
pp. 365-370
Author(s):  
Assia Eljaafari ◽  
Pierre Miossec
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
T Cell Response ◽  
Th2 Cells ◽  
Cell Mediated Immunity ◽  
Effector Cells ◽  
Therapeutic Tools ◽  
Bacteria And Fungi ◽  
Epithelial Layers

The adaptive T-cell response represents the most sophisticated component of the immune response. Foreign invaders are recognized first by cells of the innate immune system. This leads to a rapid and non-specific inflammatory response, followed by induction of the adaptive and specific immune response. Different adaptive responses can be promoted, depending on the predominant effector cells that are involved, which themselves depend on the microbial/antigen stimuli. As examples, Th1 cells contribute to cell-mediated immunity against intracellular pathogens, Th2 cells protect against parasites, and Th17 cells act against extracellular bacteria and fungi that are not cleared by Th1 and Th2 cells. Among the new subsets, Th22 cells protect against disruption of epithelial layers secondary to invading pathogens. Finally these effector subsets are regulated by regulatory T cells. These T helper subsets counteract each other to maintain the homeostasis of the immune system, but this balance can be easily disrupted, leading to chronic inflammation or autoimmune diseases. The challenge is to detect early changes in this balance, prior to its clinical expression. New molecular tools such as microarrays could be used to determine the predominant profile of the immune effector cells involved in a disease process. Such understanding should provide better therapeutic tools to counteract deregulated effector cells.

scholarly journals Sustained High Frequencies of Specific CD4 T Cells Restricted to a Single Persistent Virus

2002 ◽  
Vol 76 (8) ◽  
pp. 3748-3755 ◽  
Author(s):  
Martina Sester ◽  
Urban Sester ◽  
Barbara Gärtner ◽  
Boris Kubuschok ◽  
Matthias Girndt ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Acute Infection ◽  
T Cell Response ◽  
Proliferative Potential ◽  
Effector Cells ◽  
High Frequencies ◽  
Persistent Virus ◽  
High Level

ABSTRACT Replication of cytomegalovirus (CMV) is largely controlled by the cellular arm of the immune response. In this study the CMV-specific CD4 T-cell response was characterized in a cohort of apparently healthy individuals. In 11% of all individuals, extremely high frequencies, between 10 and 40%, were found. High-level frequencies of CMV-specific CD4 T cells persisted over several months and were not the result of an acute infection. Specific T cells were oligoclonal and were phenotypically and functionally characterized as mature effector cells, with both cytokine-secreting and proliferative potential. These high-level frequencies do not seem to compromise the immune response towards heterologous infections, and no signs of immunopathology were observed. Whereas a large temporary expansion of virus-specific T cells is well known to occur during acute infection, we now show that extremely high frequencies of virus-specific T cells may continuously exist in chronic CMV infection without overtly compromising the remaining protective immunity.

scholarly journals Regulation of T Cells in Cancer by Nitric Oxide

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2655
Author(s):  
Inesa Navasardyan ◽  
Benjamin Bonavida
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Functions

The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.

scholarly journals Generation of CD8+ T cell–mediated immunity against idiotype-negative lymphoma escapees

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4477-4485 ◽  
Author(s):  
Bindu Varghese ◽  
Adam Widman ◽  
James Do ◽  
Behnaz Taidi ◽  
Debra K. Czerwinski ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Antibody Therapy ◽  
B Cell Lymphoma ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Mediated Immunity

AbstractWe investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed. The escaping surface IgG-negative tumor cells were resistant to both antibody-dependent cellular cytotoxicity and signaling-induced cell death. Addition of intratumoral CpG to antibody therapy cured large established tumors and prevented the occurrence of tumor escapees. The failure of the combination therapy in mice deficient for CD8+ T cells demonstrates the critical role of CD8+ T cells in tumor eradication. When mice were inoculated with 2 tumors and treated systemically with antibody followed by intratumoral CpG in just one tumor, both tumors regressed, indicating that a systemic immune response was generated. Although antibody therapy can eliminate tumor cells bearing the target antigen, it frequently selects for antigen loss variants. However, when a poly-specific T-cell response was generated against the tumor by intratumoral CpG, even large established tumors were cured. Such an immune response can prevent the emergence of antibody selected tumor escapees and provide long-lasting tumor protection.

scholarly journals Chemokines are Underestimated in Preventing the Metastasizing and the Immune Elimination of Ovarian Cancer

2019 ◽  
Author(s):  
Ruurd Torensma ◽  
Petra Zusterzeel
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Adaptive Immune Response ◽  
Inhibitory Response ◽  
T Cell Response ◽  
Activated T Cells ◽  
Adaptive Immune

Nowadays the positive immune involvement in the eradication of tumor cells is assigned to the adaptive immune response. By awakening of in vivo responding T cells that are suppressed by the tumor and prevents immunological cure of the cancer. The adaptive immune response is a complex of different cells and protein molecules. Normally activated T cells are well-ordered by several late occurring inhibitors to contain the response to the unknown invaders and spare the normal cells. The tumor strengthens this inhibitory response to escape from immune elimination. Immunotherapy is to unleash the full capacity of the adaptive immune system by blocking this inhibitor response by monoclonal antibodies but with the potential drawback of autoimmune phenomena. Seen the success of the immunotherapy another feature of the immune system is overlooked. Cytokines and chemokines became in oblivion after their suspected necrosis of the tumor (TNF) did not fulfil their initial hope. When patients seek help for their complaints the ovarian cancer is in most cases already metastasized to the peritoneum and omentum. Here, we show that on the one hand chemokines produced by Th2, CD8 and NK cells inhibit cancer spreading and thus leads to a better operability and thus better survival. On the other hand, chemokine receptors are expressed by the tumor that are a decoy by binding chemokines that normally should attract antigen cross-presenting dendritic cells, which start an adaptive T cell response.

scholarly journals Differential combination immunotherapy requirements for inflamed (warm) tumors versus T cell excluded (cool) tumors: engage, expand, enable, and evolve

2021 ◽  
Vol 9 (2) ◽  
pp. e001691
Author(s):  
Kellsye P Fabian ◽  
Michelle R Padget ◽  
Rika Fujii ◽  
Jeffrey Schlom ◽  
James W Hodge
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Response ◽  
Metastatic Tumor ◽  
Tumor Models ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Anti Tumor Activity

BackgroundDifferent types of tumors have varying susceptibility to immunotherapy and hence require different treatment strategies; these cover a spectrum ranging from ‘hot’ tumors or those with high mutational burden and immune infiltrates that are more amenable to targeting to ‘cold’ tumors that are more difficult to treat due to the fewer targetable mutations and checkpoint markers. We hypothesized that an effective anti-tumor response requires multiple agents that would (1) engage the immune response and generate tumor-specific effector cells; (2) expand the number and breadth of the immune effector cells; (3) enable the anti-tumor activity of these immune cells in the tumor microenvironment; and (4) evolve the tumor response to widen immune effector repertoire.MethodsA hexatherapy combination was designed and administered to MC38-CEA (warm) and 4T1 (cool) murine tumor models. The hexatherapy regimen was composed of adenovirus-based vaccine and IL-15 (interleukin-15) superagonist (N-803) to engage the immune response; anti-OX40 and anti-4-1BB to expand effector cells; anti-PD-L1 (anti-programmed death-ligand 1) to enable anti-tumor activity; and docetaxel to promote antigen spread. Primary and metastatic tumor growth inhibition were measured. The generation of anti-tumor immune effector cells was analyzed using flow cytometry, ELISpot (enzyme-linked immunospot), and RNA analysis.ResultsThe MC38-CEA and 4T1 tumor models have differential sensitivities to the combination treatments. In the ‘warm’ MC38-CEA, combinations with two to five agents resulted in moderate therapeutic benefit while the hexatherapy regimen outperformed all these combinations. On the other hand, the hexatherapy regimen was required in order to decrease the primary and metastatic tumor burden in the ‘cool’ 4T1 model. In both models, the hexatherapy regimen promoted CD4+ and CD8+ T cell proliferation and activity. Furthermore, the hexatherapy regimen induced vaccine-specific T cells and stimulated antigen cascade. The hexatherapy regimen also limited the immunosuppressive T cell and myeloid derived suppressor cell populations, and also decreased the expression of exhaustion markers in T cells in the 4T1 model.ConclusionThe hexatherapy regimen is a strategic combination of immuno-oncology agents that can engage, expand, enable, and evolve the immune response and can provide therapeutic benefits in both MC38-CEA (warm) and 4T1 (cool) tumor models.

scholarly journals The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian-Yu Lei ◽  
Ying-Ze Ye ◽  
Xi-Qun Zhu ◽  
Daniel Smerin ◽  
Li-Juan Gu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Ischaemic Stroke ◽  
Immune Cells ◽  
Tissue Injury ◽  
Recovery Period ◽  
Vital Functions ◽  
Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

scholarly journals TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Anupam Kumar ◽  
Katharine Chen ◽  
Claudia Petritsch ◽  
Theodore Nicolaides ◽  
Mariarita Santi-Vicini ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Lower Grade ◽  
Functional Relationships

Abstract The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals Quantitative analysis of the CD8 + T–cell response to readily eliminated and persistent viruses

2000 ◽  
Vol 355 (1400) ◽  
pp. 1093-1101 ◽  
Author(s):  
P. C. Doherty ◽  
J. M. Riberdy ◽  
G. T. Belz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Flow Cytometric Analysis ◽  
T Cell Response ◽  
Basic Question ◽  
Cell Mediated Immunity ◽  
Specific Response ◽  
Turnover Rates

The recent development of techniques for the direct staining of peptide–specific CD8 + T cells has revolutionized the analysis of cell–mediated immunity (CMI) in virus infections. This approach has been used to quantify the acute and long–term consequences of infecting laboratory mice with the readily eliminated influenza A viruses (fluA) and a persistent γherpesvirus (γHV). It is now, for the first time, possible to work with real numbers in the analysis of CD8 + T CMI, and to define various characteristics of the responding lymphocytes both by direct flow cytometric analysis and by sorting for further in vitro manipulation. Relatively little has yet been done from the latter aspect, though we are rapidly accumulating a mass of numerical data. The acute, antigen–driven phases of the fluA and γHV–specific response look rather similar, but CD8 + T–cell numbers are maintained in the long term at a higher ‘set point’ in the persistent infection. Similarly, these ‘memory’ T cells continue to divide at a much greater rate in the γHV–infected mice. New insights have also been generated on the nature of the recall response following secondary challenge in both experimental systems, and the extent of protection conferred by large numbers of virus–specific CD8 + T cells has been determined. However, there are still many parameters that have received little attention, partly because they are difficult to measure. These include the rate of antigen–specific CD8 + T–cell loss, the extent of the lymphocyte ‘diaspora’ to other tissues, and the diversity of functional characteristics, turnover rates, clonal life spans and recirculation profiles. The basic question for immunologists remains how we reconcile the extraordinary plasticity of the immune system with the mechanisms that maintain a stable milieu interieur. This new capacity to quantify CD8 + T–cell responses in readily manipulated mouse models has obvious potential for illuminating homeostatic control, particularly if the experimental approaches to the problem are designed in the context of appropriate predictive models.

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