scholarly journals Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

2015 ◽  
Vol 112 (48) ◽  
pp. 14942-14947 ◽  
Author(s):  
Dapeng Yan ◽  
Julia Farache ◽  
Michael Mingueneau ◽  
Diane Mathis ◽  
Christophe Benoist
Keyword(s):  
T Cells ◽  
T Cell Receptor ◽  
Transcriptome Profiling ◽  
Cell Receptor ◽  
Treg Cells ◽  
Immunological Tolerance ◽  
Calcium Flux ◽  
Transcriptional Signature ◽  
Tcr Signals ◽  
Deficient Mice

FoxP3+ T regulatory (Treg) cells have a fundamental role in immunological tolerance, with transcriptional and functional phenotypes that demarcate them from conventional CD4+ T cells (Tconv). Differences between these two lineages in the signaling downstream of T-cell receptor-triggered activation have been reported, and there are different requirements for some signaling factors. Seeking a comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes upon TCR-mediated activation, with low phosphorylation of CD3ζ, SLP76, Erk1/2, AKT, or S6 and lower calcium flux. In contrast, STAT phosphorylation triggered by interferons, IL2 or IL6, showed variations between Treg and Tconv in magnitude or choice of preferential STAT activation but no general Treg signaling defect. Much, but not all, of the Treg/Tconv difference in TCR-triggered responses could be attributed to lower responsiveness of antigen-experienced cells with CD44hi or CD62Llo phenotypes, which form a greater proportion of the Treg pool. Candidate regulators were tested, but the Treg/Tconv differential could not be explained by overexpression in Treg cells of the signaling modulator CD5, the coinhibitors PD-1 and CTLA4, or the regulatory phosphatase DUSP4. However, transcriptome profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, which partially overlaps with the TCR-dependent Treg gene set. Thus, Treg cells, likely because of their intrinsically higher reactivity to self, tune down TCR signals but seem comparatively more attuned to cytokines or other intercellular signals.

scholarly journals T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse

2011 ◽  
Vol 208 (6) ◽  
pp. 1279-1289 ◽  
Author(s):  
Amy E. Moran ◽  
Keli L. Holzapfel ◽  
Yan Xing ◽  
Nicole R. Cunningham ◽  
Jonathan S. Maltzman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Antigen Receptor ◽  
Cell Receptor ◽  
Treg Cells ◽  
Receptor Activation ◽  
Early Gene ◽  
Inkt Cells ◽  
Tcr Signals

The ability of antigen receptors to engage self-ligands with varying affinity is crucial for lymphocyte development. To further explore this concept, we generated transgenic mice expressing GFP from the immediate early gene Nr4a1 (Nur77) locus. GFP was up-regulated in lymphocytes by antigen receptor stimulation but not by inflammatory stimuli. In T cells, GFP was induced during positive selection, required major histocompatibility complex for maintenance, and directly correlated with the strength of T cell receptor (TCR) stimulus. Thus, our results define a novel tool for studying antigen receptor activation in vivo. Using this model, we show that regulatory T cells (Treg cells) and invariant NKT cells (iNKT cells) perceived stronger TCR signals than conventional T cells during development. However, although Treg cells continued to perceive strong TCR signals in the periphery, iNKT cells did not. Finally, we show that Treg cell progenitors compete for recognition of rare stimulatory TCR self-ligands.

scholarly journals Loss of tonic T-cell receptor signals alters the generation but not the persistence of CD8+ memory T cells

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5560-5570 ◽  
Author(s):  
Karla R. Wiehagen ◽  
Evann Corbo ◽  
Michelle Schmidt ◽  
Haina Shin ◽  
E. John Wherry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Sh2 Domain ◽  
Normal Numbers ◽  
Tcr Signaling ◽  
Tcr Signals

Abstract The requirements for tonic T-cell receptor (TCR) signaling in CD8+ memory T-cell generation and homeostasis are poorly defined. The SRC homology 2 (SH2)-domain–containing leukocyte protein of 76 kDa (SLP-76) is critical for proximal TCR-generated signaling. We used temporally mediated deletion of SLP-76 to interrupt tonic and activating TCR signals after clearance of the lymphocytic choriomeningitis virus (LCMV). SLP-76–dependent signals are required during the contraction phase of the immune response for the normal generation of CD8 memory precursor cells. Conversely, LCMV-specific memory CD8 T cells generated in the presence of SLP-76 and then acutely deprived of TCR-mediated signals persist in vivo in normal numbers for more than 40 weeks. Tonic TCR signals are not required for the transition of the memory pool toward a central memory phenotype, but the absence of SLP-76 during memory homeostasis substantially alters the kinetics. Our data are consistent with a model in which tonic TCR signals are required at multiple stages of differentiation, but are dispensable for memory CD8 T-cell persistence.

Individual and Population Quantitative Analyses of Calcium Flux in T-Cells Activated on Functionalized Material Surfaces

2012 ◽  
Vol 65 (1) ◽  
pp. 45 ◽  
Author(s):  
Susan N. Christo ◽  
Ghafar.T. Sarvestani ◽  
Stefani S. Griesser ◽  
Bryan R. Coad ◽  
Hans J. Griesser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Quantitative Measure ◽  
Cell Receptor ◽  
Population Based ◽  
Calcium Flux ◽  
Material Surfaces ◽  
Quantitative Analyses ◽  
Novel Method

We have developed a novel method for activating T-cells on material surfaces that enable individual and population-based analyses of intracellular calcium flux, as a quantitative measure of T-cell receptor engagement. Functionalized material surfaces were created using a plasma-polymerized foundation layer to immobilize stimulatory T-cell ligands, which could induce T-cell receptor-dependent calcium flux in naive T-cells. Real-time confocal microscopic detection and quantification of calcium flux using paired fluorescent ratiometric probes facilitated the tracking and analysis of response profiles of individual T-cells, as well as population analyses using a combination of individual T-cell events. This type of combined analysis cannot be achieved using traditional population-based flow cytometric approaches, and thus provides a logical step towards developing the capacity to assess the magnitude and quality of inherently heterogeneous effector T-cell responses to antigenic challenge.

scholarly journals Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells

2014 ◽  
Vol 211 (3) ◽  
pp. 529-543 ◽  
Author(s):  
Julio Gomez-Rodriguez ◽  
Elizabeth A. Wohlfert ◽  
Robin Handon ◽  
Françoise Meylan ◽  
Julie Z. Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Mammalian Target Of Rapamycin ◽  
Cell Receptor ◽  
Treg Cells ◽  
Cytokine Signaling

A proper balance between Th17 and T regulatory cells (Treg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk−/− CD4+ T cells develop higher percentages of functional FoxP3+ cells, associated with increased sensitivity to IL-2. Itk−/− CD4+ T cells also preferentially develop into Treg cells in vivo. We find that Itk-deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk−/− cells also exhibit reduced IL-2–induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4+ T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk-deficient CD4+ T cells show impaired TCR-mediated induction of Myc and miR-19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells.

scholarly journals Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways

2002 ◽  
Vol 195 (9) ◽  
pp. 1103-1114 ◽  
Author(s):  
Lucinda F. Reynolds ◽  
Lesley A. Smyth ◽  
Trisha Norton ◽  
Norman Freshney ◽  
Julian Downward ◽  
...  
Keyword(s):  
T Cell ◽  
Phospholipase C ◽  
T Cell Receptor ◽  
Genetic System ◽  
Cell Receptor ◽  
Calcium Flux ◽  
Double Positive ◽  
Signaling Complex ◽  
Tcr Signals ◽  
Phosphoinositide 3 Kinase

Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4+CD8+ double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-γ1 (PLCγ1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCγ1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCγ1 and the adaptor molecule Src homology 2 domain–containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.

Thymic selection and peptide-induced activation of T cell receptor-transgenic CD8 T cells in interleukin-2-deficient mice

1994 ◽  
Vol 24 (10) ◽  
pp. 2317-2322 ◽  
Author(s):  
Susanne Krämer ◽  
Clio Mamalaki ◽  
Ivan Horak ◽  
Anneliese Schimpl ◽  
Dimitris Kioussis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Thymic Selection ◽  
Deficient Mice

scholarly journals Generation of Novel Traj18-Deficient Mice Lacking Vα14 Natural Killer T Cells with an Undisturbed T Cell Receptor α-Chain Repertoire

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0153347 ◽  
Author(s):  
Nyambayar Dashtsoodol ◽  
Tomokuni Shigeura ◽  
Ritsuko Ozawa ◽  
Michishige Harada ◽  
Satoshi Kojo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Natural Killer T Cells ◽  
Α Chain ◽  
Killer T Cells ◽  
Deficient Mice ◽  
Natural Killer T

scholarly journals The Single Positive T Cells Found in CD3-ζ/η−/− Mice Overtly React with Self–Major Histocompatibility Complex Molecules upon Restoration of Normal Surface Density of T Cell Receptor–CD3 Complex

1997 ◽  
Vol 185 (4) ◽  
pp. 707-716 ◽  
Author(s):  
Shih-Yao Lin ◽  
Laurence Ardouin ◽  
Anne Gillet ◽  
Marie Malissen ◽  
Bernard Malissen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Receptors ◽  
Cell Receptor ◽  
Normal Density ◽  
Cell Receptors ◽  
Peripheral T Cells ◽  
Single Positive ◽  
Deficient Mice

CD3-ζ/η–deficient mice have small thymuses containing cells that show a profound reduction in the surface levels of T cell receptors and terminate their differentiation at the CD4+CD8+ stage. Rather unexpectedly, CD3− or very low single positive T cells accumulate over time in the spleen and lymph nodes of CD3-ζ/η–deficient mice after a process dependent on MHC expression. Fusion of these peripheral T cells with a CD3-ζ–positive derivative of the BW5147 TCR-α−/β− thymoma resulted in hybridomas that do express an heterogeneous set of T cell receptor α/β dimers at their surface and at density comparable to those found in hybridomas derived from wild-type peripheral T cells. We have investigated the specificities of these T cell receptors using spleen cells from congenic and mutant mouse strains, and showed that the majority of them readily recognized self-MHC class I or class II molecules. These results demonstrate that by increasing the density and/or output of the T cell receptors expressed in peripheral T cells, one can confer them with the capacity to respond to normal density of self-MHC molecules.

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