scholarly journals A Key Role for NF-κB Transcription Factor c-Rel in T-Lymphocyte-Differentiation and Effector Functions

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Alexander Visekruna ◽  
Anton Volkov ◽  
Ulrich Steinhoff
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Cell Types ◽  
T Cell Differentiation ◽  
Effector Functions ◽  
Pathological Conditions ◽  
Precursor Proteins ◽  
Adoptive Immunity ◽  
Factor C ◽  
Antigen Presenting

The transcription factors of the Rel/NF-κB family function as key regulators of innate and adoptive immunity. Tightly and temporally controlled activation of NF-κB-signalling pathways ensures prevention of harmful immune cell dysregulation, whereas a loss of control leads to pathological conditions such as severe inflammation, autoimmune disease, and inflammation-associated oncogenesis. Five family members have been identified in mammals: RelA (p65), c-Rel, RelB, and the precursor proteins NF-κB1 (p105) and NF-κB2 (p100), that are processed into p50 and p52, respectively. While RelA-containing dimers are present in most cell types, c-Rel complexes are predominately found in cells of hematopoietic origin. In T-cell lymphocytes, certain genes essential for immune function such asIl2andFoxp3are directly regulated by c-Rel. Additionally, c-Rel-dependent IL-12 and IL-23 transcription by macrophages and dendritic cells is crucial for T-cell differentiation and effector functions. Accordingly, c-Rel expression in T cells and antigen-presenting cells (APCs) controls a delicate balance between tolerance and immunity. This review gives a selective overview on recent progress in understanding of diverse roles of c-Rel in regulating adaptive immunity.

scholarly journals NFATc1 promotes anti-tumoral effector functions and memory CD8+ T cell differentiation during non-small cell lung cancer development

2018 ◽  
pp. canres.3297.2017 ◽  
Author(s):  
Lisanne Heim ◽  
Juliane Friedrich ◽  
Marina Engelhardt ◽  
Denis I Trufa ◽  
Carol I. Geppert ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Differentiation ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cd8 T Cell ◽  
Small Cell ◽  
T Cell Differentiation ◽  
Cancer Development ◽  
Small Cell Lung ◽  
Effector Functions

scholarly journals Distinct Roles of α7 nAChRs in Antigen-Presenting Cells and CD4+ T Cells in the Regulation of T Cell Differentiation

2019 ◽  
Vol 10 ◽  
Author(s):  
Masato Mashimo ◽  
Masayo Komori ◽  
Yuriko Y. Matsui ◽  
Mami X. Murase ◽  
Takeshi Fujii ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
T Cell Differentiation ◽  
Antigen Presenting ◽  
Α7 Nachrs

scholarly journals H-2-controlled suppression of T cell response to lactate dehydrogenase B. Characterization of the lactate dehydrogenase B suppressor pathway.

1982 ◽  
Vol 156 (3) ◽  
pp. 822-833 ◽  
Author(s):  
C N Baxevanis ◽  
N Ishii ◽  
Z A Nagy ◽  
J Klein
Keyword(s):  
Lactate Dehydrogenase ◽  
T Cell ◽  
Cell Response ◽  
Cell Types ◽  
T Cell Response ◽  
T Helper ◽  
Th Cells ◽  
Th Cell ◽  
Antigen Presenting

We characterized the cell types involved in the H-2-controlled suppression of T cell response to lactate dehydrogenase B (LDHB). The suppressor effector (Tse) was found to be an Lyt-1+2+, J+ cell that recognizes antigen together with Ek molecules of antigen-presenting cells (APC). To become functional, the Tse cell requires a second signal from a nonspecific, Lyt-1+2-, J+ suppressor-inducer (Tsi) cell. The Tsi-Tse interaction is not subject to any genetic restriction. The target cell of suppression is an Lyt-1+2-, J- (most likely T helper [Th]) cell that recognizes LDHB in the context of A molecules on APC. The suppression is manifested in inhibition of the antigen-specific, A-restricted proliferation of Th cells. The interaction between Tse and Th is restricted by the A region of the H-2 complex. Because this restriction is determined by the receptor of Th cells, the mechanism of Th-Tse interaction most likely involves a concomitant recognition of LDHB and A region-controlled molecules by Th cells on the surface of Tse cells.

Adhesion of human T cells to antigen-presenting cells through SIRPβ2-CD47 interaction costimulates T-cell proliferation

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2421-2427 ◽  
Author(s):  
Laura Piccio ◽  
William Vermi ◽  
Kent S. Boles ◽  
Anja Fuchs ◽  
Carey A. Strader ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
Cell Types ◽  
Orphan Receptor ◽  
T Cell Proliferation ◽  
Central Nervous Systems ◽  
And Function ◽  
Antigen Presenting

AbstractSignal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPα binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPβ1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPβ2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPβ2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPα, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPβ2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.

scholarly journals Presentation of Toxoplasma gondii Antigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

2007 ◽  
Vol 75 (11) ◽  
pp. 5200-5209 ◽  
Author(s):  
Florence Dzierszinski ◽  
Marion Pepper ◽  
Jason S. Stumhofer ◽  
David F. LaRosa ◽  
Emma H. Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Antigen Processing ◽  
Cell Types ◽  
T Cell Response ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Antigen Presenting

ABSTRACT Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8+ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8+ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8+ T cells during toxoplasmosis.

scholarly journals IMMU-08. MICROENVIRONMENT MODULATION BY TIM-3 BLOCKADE IMPROVES THE OUTCOME OF PRECLINICAL DIPG MODELS

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i28-i28
Author(s):  
Iker Ausejo-Mauleon ◽  
Sara Labiano ◽  
Virginia Laspidea ◽  
Marc Garcia-Moure ◽  
Daniel de la Nava ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Pediatric Brain Tumors ◽  
Immune Memory ◽  
Cd8 Cells ◽  
Functional Studies

Abstract Diffuse Midline Gliomas (DMGs), encompassing Diffuse Intrinsic Pontine Gliomas (DIPGs), are the most aggressive pediatric brain tumors. Their meagre survival has not changed despite the combination of radiotherapy with targeted therapies emphasizing the urgent need for effective treatments. Recent research suggested that the DIPG tumor microenvironment is neither highly immunosuppressive nor inflammatory. These analyses showed the lack of infiltrating lymphocytes and the abundance of CD11b+ cells. TIM-3 (HAVCR2) is a member of the T-cell immunoglobulin and mucin domain protein family which is expressed on multiple immune cell types including T cells, Tregs, NK cells, monocytes, dendritic cells and microglia, where it potently regulates not only adaptive immunity but also innate immunity. Therefore, the central hypothesis of this study is that TIM-3 inhibitors could stimulate a cytotoxic immune effect and challenge several components in the tumor microenvironment including microglia, thereby providing a potential effective treatment for DMGs. In silico assessment of TIM-3 expression in a DIPG datasets showed a robust expression of this gene. Moreover, single-cell sequencing analyses of DIPG biopsies uncover its expression on tumor cells, especially in the OPCs compartment. In vivo efficacy studies showed that treatment with anti-TIM-3 antibody significantly increase the overall survival in two DIPG immunocompetent orthotopic animal models (doubling the median), lead to long-term survivors (50%) and showed immune memory. Analyses of CD45+ populations in the tumor microenvironment showed a significant increase in B, NK and CD8+ cells corresponding with a T-cell activate phenotype in treated-mice. The potential therapeutic involvement of NK cells was certified using nude mice and functional studies. Involvement of microglia in currently being analysed. In summary, these data underscore TIM-3 as a potential target DIPGs and uncover the potential involvement of NKs and other immune mechanisms in the efficacy of anti-TIM-3 therapy.

scholarly journals Regulation of Th1 T Cell Differentiation by Iron via Upregulation of T Cell Immunoglobulin and Mucin Containing Protein-3 (TIM-3)

2021 ◽  
Vol 12 ◽  
Author(s):  
Christa Pfeifhofer-Obermair ◽  
Piotr Tymoszuk ◽  
Manfred Nairz ◽  
Andrea Schroll ◽  
Gloria Klais ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Iron Supplementation ◽  
Immune Cell ◽  
Cell Subset ◽  
Essential Element ◽  
T Cell Differentiation ◽  
Intracellular Pathogens ◽  
Iron Loading

Iron plays an important role in host–pathogen interactions, in being an essential element for both pathogen and host metabolism, but also by impacting immune cell differentiation and anti-microbial effector pathways. Iron has been implicated to affect the differentiation of T lymphocytes during inflammation, however, so far the underlying mechanism remained elusive. In order to study the role of iron in T cell differentiation we here investigated how dietary iron supplementation affects T cell function and outcome in a model of chronic infection with the intracellular bacterium Salmonella enterica serovar typhimurium (S. Typhimurium). Iron loading prior to infection fostered bacterial burden and, unexpectedly, reduced differentiation of CD4+ T helper cells type 1 (Th1) and expression of interferon-gamma (IFNγ), a key cytokine to control infections with intracellular pathogens. This effect could be traced back to iron-mediated induction of the negative immune checkpoint regulator T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), expressed on the surface of this T cell subset. In vitro experiments demonstrated that iron supplementation specifically upregulated mRNA and protein expression of TIM-3 in naïve Th cells in a dose-depdendent manner and hindered priming of those T cells towards Th1 differentiation. Importantly, administration of TIM-3 blocking antibodies to iron-loaded mice infected with S. Typhimurium virtually restored Th1 cell differentiation and significantly improved bacterial control. Our data uncover a novel mechanism by which iron modulates CD4+ cell differentiation and functionality and hence impacts infection control with intracellular pathogens. Specifically, iron inhibits the differentiation of naive CD4+ T cells to protective IFNγ producing Th1 lymphocytes via stimulation of TIM-3 expression. Finally, TIM-3 may serve as a novel drug target for the treatment of chronic infections with intracellular pathogens, specifically in iron loading diseases.

scholarly journals Higher cytolytic score correlates with an immunosuppressive tumor microenvironment and reduced survival in glioblastoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alexander F. Haddad ◽  
Jia-Shu Chen ◽  
Taemin Oh ◽  
Matheus P. Pereira ◽  
Rushikesh S. Joshi ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Cell Types ◽  
Cd8 T Cell ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Sequencing Data ◽  
Gene Score ◽  
T Cell Infiltration ◽  
The Relationship

Abstract Cytolytic score (CYT), calculated from mRNA expression levels of granzyme and perforin, positively correlates with CD8+ T cell infiltration/activity in a variety of cancers. Unlike other cancers, higher CYT has been associated with worse prognosis in glioblastoma (GBM). To address this discrepancy, we sought to investigate the relationship between CYT and immune checkpoint gene score (ICGscore), as well as their correlation with patient survival and tumor immune cell infiltration. Clinical and RNA-sequencing data for patients with newly diagnosed GBM were obtained from The Cancer Genome Atlas. Maximally-selected rank statistics was used to dichotomize subgroups. CIBERSORT was used to estimate abudence of immune cell-types. Spearman correlation was used to characterize the relationship between CYT and ICGscore. Kaplan–Meier curves were generated for survival analysis. Overall, 28/151 patients had high CYT. High CYT was associated with a mesenchymal subtype (p < 0.001) and worse survival (7.45 vs. 12.2 months, p < 0.001). There were no differences in patient demographics, IDH/MGMT mutation status, or treatment. On subgroup analysis, patients with high CYT/ICGscore had significantly increased CD8+ infiltration (p < 0.001), as expected, and worse survival (HR 0.445, p < 0.01). Furthermore, CYT strongly correlated with ICGscore (RS = 0.675, p < 0.001). The high CYT/ICGscore subgroup was associated with greater infiltration of M2 macrophages (p = 0.011) and neutrophils (p = 0.055). Our study highlights a multidimensional immunosuppressive GBM microenvironment in patients with higher CYT and potentially identifies patients with high CYT/ICGscore as a subgroup that may particularly benefit from multi-faceted immunotherapies, given their already elevated tumor CD8+ T cell levels.

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