scholarly journals Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

2019 ◽  
Author(s):  
Rajesh Lamichhane ◽  
Marion Schneider ◽  
Sara M. de la Harpe ◽  
Thomas W. R. Harrop ◽  
Rachel F. Hannaway ◽  
...  
Keyword(s):  
Immune Response ◽  
Transcription Factor ◽  
T Cell ◽  
Cell Receptor ◽  
Transcriptional Analysis ◽  
Mait Cells ◽  
Cytokines And Chemokines ◽  
Factor Expression ◽  
Transcription Factor Expression

AbstractMAIT cells are an abundant innate-like T cell population which can be activated via either their T cell receptor (TCR), which recognizes MR1-bound pyrimidine antigens derived from microbial riboflavin biosynthesis, or via cytokines, such as IL-12 and IL-18. In vivo, these two modes of activation may act in concert or independently depending upon the nature of the microbial or inflammatory stimuli. It is unknown, however, how the MAIT cell response differs to the different modes of activation. Here, we define the transcriptional and effector responses of human MAIT cells to TCR and cytokine stimulation. We report that MAIT cells rapidly respond to TCR stimulation through the production of multiple effector cytokines and chemokines, alteration of their cytotoxic granule content and transcription factor expression, and upregulation of co-stimulatory proteins CD40L and 4-1BB. In contrast, cytokine-mediated activation is slower and results in more limited production of cytokines, chemokines, and co-stimulatory proteins; differences in granule content and transcription factor expression are also evident. Therefore, we propose that in infections by riboflavin-synthesizing bacteria, MAIT cells play a key early role in effecting and coordinating the immune response, while in the absence of TCR stimulation (e.g. viral infection) their role is likely to differ.

Transcription Factor Expression in Cell Lines Derived from Natural Killer-Cell and Natural Killer-Like T-Cell Leukemia-Lymphoma

Human Cell ◽  
2008 ◽  
Vol 17 (2) ◽  
pp. 85-92 ◽  
Author(s):  
Yoshinobu MATSUO ◽  
Hans G. DREXLER ◽  
Akira HARASHIMA ◽  
Ayumi OKOCHI ◽  
Norio SHIMIZU ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Cell Lines ◽  
Killer Cell ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Factor Expression ◽  
Transcription Factor Expression

scholarly journals Characterization of CD8+ T Cell Differentiation following SIVΔnef Vaccination by Transcription Factor Expression Profiling

2015 ◽  
Vol 11 (3) ◽  
pp. e1004740 ◽  
Author(s):  
James M. Billingsley ◽  
Premeela A. Rajakumar ◽  
Michelle A. Connole ◽  
Nadine C. Salisch ◽  
Sama Adnan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
T Cell ◽  
Expression Profiling ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Factor Expression ◽  
Transcription Factor Expression

scholarly journals Calcium Regulation of GM-CSF by Calmodulin-Dependent Kinase II Phosphorylation of Ets1

2002 ◽  
Vol 13 (12) ◽  
pp. 4497-4507 ◽  
Author(s):  
Hebin Liu ◽  
Thomas Grundström
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
T Cell Receptor ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Wild Type ◽  
Gm Csf

The multipotent cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) is involved in particular in the physiological response to infection and in inflammatory responses. GM-CSF is produced by many cell types, including T lymphocytes responding to T-cell receptor activation and mantle zone B lymphocytes. B-cell receptor and T-cell receptor activation generates two major signals: an increase in intracellular Ca2+concentration and a protein kinase cascade. Previous studies have shown that the Ca2+/calmodulin-dependent phosphatase calcineurin mediates stimulation of GM-CSF transcription in response to Ca2+. In this study, we show that Ca2+signaling also regulates GM-CSF transcription negatively through Ca2+/calmodulin-dependent kinase II (CaMK II) phosphorylation of serines in the autoinhibitory domain for DNA binding of the transcription factor Ets1. Wild-type Ets1 negatively affects GM-CSF transcription on Ca2+stimulation in the presence of cyclosporin A, which inhibits calcineurin. Conversely, Ets1 with mutated CaMK II target serines showed an increase in transactivation of the GM-CSF promoter/enhancer. Moreover, constitutively active CaMK II inhibited transactivation of GM-CSF by wild-type Ets1 but not by Ets1 with mutated CaMK II sites. Mutation of CaMK II target serines in Ets1 also relieves inhibition of cooperative transactivation of GM-CSF with the Runx1/AML1 transcription factor. In addition, the Ca2+-dependent phosphorylation of Ets1 reduces the binding of Ets1 to the GM-CSF promoter in vivo.

scholarly journals Anti-CD2 antibodies induce T cell unresponsiveness in vivo.

1991 ◽  
Vol 174 (5) ◽  
pp. 957-967 ◽  
Author(s):  
B Gückel ◽  
C Berek ◽  
M Lutz ◽  
P Altevogt ◽  
V Schirrmacher ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Cell Line ◽  
Cell Receptor ◽  
T Cell Response ◽  
Signal Molecule

The CD2 receptor functions as an adhesion and signal molecule in T cell recognition. Multimeric binding of CD2 on T cells to its physiologic ligand LFA-3 on cognate partner cells in vitro efficiently augments the antigen-specific T cell signal delivered by the T cell receptor/CD3 complex. The precise contribution of the antigen-nonspecific CD2-LFA-3 interactions to T cell immune responses in vivo, however, has been difficult to assess. Here we analyzed the role of CD2 in the murine immune response using a nondepleting anti-CD2 monoclonal antibody that induces a marked, reversible modulation of CD2 expression on murine T and B cells in situ. This modulation is dose and time dependent, specific for CD2, and does not require the Fc portion of the antibody. Anti-CD2 antibodies [rat IgG1 or F(ab')2] significantly inhibit the CD4+ T cell-mediated response to hen egg lysozyme and the cytotoxic CD8+ T cell response to a syngeneic tumor cell line. In both cases, anti-CD2 antibodies are only effective when administered before or within 24 h after antigen priming. The suppression of the antitumor response corresponds to a sixfold reduction of specific cytotoxic T lymphocyte precursor cells and results in the abrogation of protective antitumor immunity. Anti-CD2 antibodies also affect the humoral immune response to oxazolone: the isotype switch from specific IgM to IgG1 antibodies is delayed, whereas the IgM response is unaltered. In addition, a single antibody injection results in sustained polyclonal unresponsiveness of T cells irrespective of antigen priming and CD2 modulation. These results document that CD2-mediated signals induce a state of T cell unresponsiveness in vivo.

scholarly journals T cell-specific deletion of Pgam1 reveals a critical role for glycolysis in T cell responses

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Koji Toriyama ◽  
Makoto Kuwahara ◽  
Hiroshi Kondoh ◽  
Takumi Mikawa ◽  
Nobuaki Takemori ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Cell Proliferation And Differentiation ◽  
Tcr Signals ◽  
Deficient Mice

AbstractAlthough the important roles of glycolysis in T cells have been demonstrated, the regulatory mechanism of glycolysis in activated T cells has not been fully elucidated. Furthermore, the influences of glycolytic failure on the T cell-dependent immune response in vivo remain unclear. We therefore assessed the role of glycolysis in the T cell-dependent immune response using T cell-specific Pgam1-deficient mice. Both CD8 and CD4 T cell-dependent immune responses were attenuated by Pgam1 deficiency. The helper T cell-dependent inflammation was ameliorated in Pgam1-deficient mice. Glycolysis augments the activation of mTOR complex 1 (mTORC1) and the T-cell receptor (TCR) signals. Glutamine acts as a metabolic hub in activated T cells, since the TCR-dependent increase in intracellular glutamine is required to augment glycolysis, increase mTORC1 activity and augment TCR signals. These findings suggest that mTORC1, glycolysis and glutamine affect each other and cooperate to induce T cell proliferation and differentiation.

scholarly journals Regulation of  T Cell Receptor δ Gene Rearrangement by CBF/PEBP2

1997 ◽  
Vol 185 (7) ◽  
pp. 1193-1202 ◽  
Author(s):  
Pilar Lauzurica ◽  
Xiao-Ping Zhong ◽  
Michael S. Krangel ◽  
Joseph L. Roberts
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Binding Site ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Vdj Recombination ◽  
Human T Cell ◽  
Transgenic Lines ◽  
Factor C

We have analyzed transgenic mice carrying versions of a human T cell receptor (TCR)-δ gene minilocus to study the developmental control of  VDJ (variable/diversity/joining) recombination. Previous data indicated that a 1.4-kb DNA fragment carrying the TCR-δ enhancer (Eδ) efficiently activates minilocus VDJ recombination in vivo. We tested whether the transcription factor CBF/PEBP2 plays an important role in the ability of Eδ to activate VDJ recombination by analyzing VDJ recombination in mice carrying a minilocus in which the δE3 element of Eδ includes a mutated CBF/PEBP2 binding site. The enhancer-dependent VD to J step of minilocus rearrangement was dramatically inhibited in three of four transgenic lines, arguing that the binding of CBF/PEBP2 plays a role in modulating local accessibility to the VDJ recombinase in vivo. Because mutation of the δE3 binding site for the transcription factor c-Myb had previously established a similar role for c-Myb, and because a 60-bp fragment of Eδ carrying δE3 and δE4 binding sites for CBF/PEBP2, c-Myb, and GATA-3 displays significant enhancer activity in transient transfection experiments, we tested whether this fragment of Eδ is sufficient to activate VDJ recombination in vivo. This fragment failed to efficiently activate the enhancerdependent VD to J step of minilocus rearrangement in all three transgenic lines examined, indicating that the binding of CBF/PEBP2 and c-Myb to their cognate sites within Eδ, although necessary, is not sufficient for the activation of VDJ recombination by Eδ. These results imply that CBF/PEBP2 and c-Myb collaborate with additional factors that bind elsewhere within Eδ to modulate local accessibility to the VDJ recombinase in vivo.

scholarly journals Th1-Biased Hepatitis C Virus-Specific Follicular T Helper-Like Cells Effectively Support B Cells After Antiviral Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Katharina Zoldan ◽  
Sabine Ehrlich ◽  
Saskia Killmer ◽  
Katharina Wild ◽  
Maike Smits ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Cd4 T Cell ◽  
Type I ◽  
T Helper ◽  
Tfh Cells ◽  
Cell Clones ◽  
Factor Expression ◽  
Transcription Factor Expression

Circulating Th1-biased follicular T helper (cTfh1) cells have been associated with antibody responses to viral infection and after vaccination but their B cell helper functionality is less understood. After viral elimination, Tfh1 cells are the dominant subset within circulating Hepatitis C Virus (HCV)-specific CD4 T cells, but their functional capacity is currently unknown. To address this important point, we established a clone-based system to evaluate CD4 T cell functionality in vitro to overcome experimental limitations associated with their low frequencies. Specifically, we analyzed the transcription factor expression, cytokine secretion and B cell help in co-culture assays of HCV- (n = 18) and influenza-specific CD4 T cell clones (n = 5) in comparison to Tfh (n = 26) and Th1 clones (n = 15) with unknown antigen-specificity derived from healthy donors (n = 4) or direct-acting antiviral (DAA)-treated patients (n = 5). The transcription factor expression and cytokine secretion patterns of HCV-specific CD4 T cell clones indicated a Tfh1 phenotype, with expression of T-bet and Bcl6 and production of IFN-γ and IL-21. Their B helper capacity was superior compared to influenza-specific or Tfh and Th1 clones. Moreover, since Tfh cells are enriched in the IFN-rich milieu of the HCV-infected liver, we investigated the impact of IFN exposure on Tfh phenotype and function. Type I IFN exposure was able to introduce similar phenotypic and functional characteristics in the Tfh cell population within PBMCs or Tfh clones in vitro in line with our finding that Tfh cells are elevated in HCV-infected patients shortly after initiation of IFN-α therapy. Collectively, we were able to functionally characterize HCV-specific CD4 T cells in vitro and not only confirmed a Tfh1 phenotype but observed superior Tfh functionality despite their Th1 bias. Furthermore, our results suggest that chronic type I IFN exposure supports the enrichment of highly functional HCV-specific Tfh-like cells during HCV infection. Thus, HCV-specific Tfh-like cells after DAA therapy may be a promising target for future vaccination design aiming to introduce a neutralizing antibody response.

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