scholarly journals Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells.

1995 ◽  
Vol 182 (5) ◽  
pp. 1591-1596 ◽  
Author(s):  
S Constant ◽  
C Pfeiffer ◽  
A Woodard ◽  
T Pasqualini ◽  
K Bottomly
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Functional Differentiation ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
Receptor Ligation

Naive CD4+ T cells can differentiate into cells predominantly involved in humoral immunity, known as T helper type 2 cells (Th2), or cells involved in cell-mediated immunity, known as Th1 cells. In this report, we show that priming of CD4+ T cells bearing a transgene-encoded T cell receptor can lead to differentiation into Th1-like cells producing abundant interferon gamma when the cells are exposed to high antigen doses, while low doses of the same peptide induce cells with the same T cell receptor to differentiate into Th2-like cells producing abundant interleukin 4. Thus antigen dose is one factor that can control the differentiation fate of a naive CD4+ T cell.

scholarly journals The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.

1992 ◽  
Vol 176 (4) ◽  
pp. 1091-1098 ◽  
Author(s):  
R A Seder ◽  
W E Paul ◽  
M M Davis ◽  
B Fazekas de St Groth
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Ifn Gamma

To study the factors that determine whether CD4+ T cells produce interleukin 4 (IL-4) or interferon gamma (IFN-gamma) upon stimulation we used a system allowing naive T cells to be primed in vitro by specific antigen. Dense CD4+ T cells were purified from mice that expressed transgenes encoding a T cell receptor specific for pigeon cytochrome C peptide 88-104 in association with I-Ek. These T cells produced very limited amounts of IL-4 and IFN-gamma upon immediate challenge with 88-104 and antigen-presenting cells (APC). However, after an initial "priming" culture in which they were incubated for 4 d in the presence of 88-104, APC, and 1,000 U/ml IL-4, the T cells acquired the capacity to produce substantial amounts of IL-4 upon rechallenge but made very little IFN-gamma. Cells primed in the absence of IL-4 produced IFN-gamma upon rechallenge but virtually no IL-4. The inhibitory effect of IL-4 on IFN-gamma production did not appear to be mediated by the induction of IL-10 production since IL-10 addition to initial cultures did not suppress priming for IFN-gamma production, nor did anti-IL-10 block the inhibitory effect of IL-4. IFN-gamma itself did not increase priming for IFN-gamma production, nor did anti-IFN-gamma reduce such priming. IFN-gamma did, however, diminish priming for IL-4 production when limiting amounts of IL-4 (100 U/ml) were used in the initial culture. The dominant effect of IL-4 in determining the lymphokine-producing phenotype of primed cells was observed with dendritic cells (DC), activated B cells, and I-Ek-transfected fibroblasts as APC. However, the different APC did vary in their potency, with DC being superior to activated B cells, which were superior to transfected fibroblasts.

scholarly journals Transient Inhibition of Interleukin 4 Signaling by T Cell Receptor Ligation

2000 ◽  
Vol 192 (8) ◽  
pp. 1125-1134 ◽  
Author(s):  
Jinfang Zhu ◽  
Hua Huang ◽  
Liying Guo ◽  
Timothy Stonehouse ◽  
Cynthia J. Watson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 4 ◽  
Interferon Α ◽  
Limiting Factor

Interleukin (IL)-4 and IL-12 together with T cell receptor (TCR) engagement are crucial for the differentiation of CD4+ T cells into T helper (Th)2 or Th1 cells, respectively. Although IL-4 receptors (IL-4Rs) but not IL-12Rs are expressed on naive CD4+ T cells, IL-4 has no apparent advantage over IL-12 in driving naive T cell differentiation when the cells are primed with both IL-4 and IL-12 in vitro. It was found that IL-4–induced phosphorylation of Janus kinases 1 and 3, IL-4Rα, signal transducer and activator of transcription 6, and insulin receptor substrate 2 was strikingly but transiently inhibited by TCR ligation both in conventional and TCR transgenic T cells. TCR engagement also blocked the expression of an IL-4–inducible gene. Signals induced by other cytokines, including IL-2, IL-6, and interferon α, but not by insulin-like growth factor 1, were also blocked by TCR engagement. The capacity of various inhibitors to reverse TCR-mediated inhibition of IL-4 signaling suggested that activation of the Ras–mitogen-activated protein kinase pathway and of the calcineurin pathway contribute to desensitizing IL-4R. IL-4 responsiveness returned at about the time (∼12 h) that IL-12–mediated signaling was first observed. Thus, through different mechanisms, neither IL-4R nor IL-12R has any clear advantage in polarizing cells; rather, the availability of cytokine is probably the limiting factor in this process.

Membranes of activated CD4+ T cells expressing T cell receptor (TcR) αβ or TcR γδ induce IgE synthesis by human B cells in the presence of interleukin-4

1992 ◽  
Vol 22 (5) ◽  
pp. 1133-1141 ◽  
Author(s):  
Hugues Gascan ◽  
Gregorio G. Aversa ◽  
Jean-Françlois Gauchat ◽  
Peter Van Vlasselaer ◽  
Maria-Grazia Roncarolo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Human B Cells ◽  
Ige Synthesis

scholarly journals Calcium-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells

2021 ◽  
Author(s):  
Bieerkehazhi Shayahati ◽  
Ying Fan ◽  
Savannah J. West ◽  
Ritika Tewari ◽  
Junsuk Ko ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Post Translational Modification ◽  
Calcium Dependent ◽  
Calmodulin Binding ◽  
Calcium Calmodulin Dependent

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21, a member of the DHHC family of mammalian protein acyltransferases, mediates T cell receptor-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice expressing a functionally deficient version of DHHC21, we show that DHHC21 is a calcium/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We found that disruption of the calcium/calmodulin binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2, and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity.

scholarly journals Ceramide Synthase 2 Null Mice Are Protected from Ovalbumin-Induced Asthma with Higher T Cell Receptor Signal Strength in CD4+ T Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2713
Author(s):  
Sun-Hye Shin ◽  
Kyung-Ah Cho ◽  
Hee-Soo Yoon ◽  
So-Yeon Kim ◽  
Hee-Yeon Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Acyl Chain ◽  
Signal Strength ◽  
Cell Receptor ◽  
Ceramide Synthase ◽  
Asthmatic Patients

(1) Background: six mammalian ceramide synthases (CerS1–6) determine the acyl chain length of sphingolipids (SLs). Although ceramide levels are increased in murine allergic asthma models and in asthmatic patients, the precise role of SLs with specific chain lengths is still unclear. The role of CerS2, which mainly synthesizes C22–C24 ceramides, was investigated in immune responses elicited by airway inflammation using CerS2 null mice. (2) Methods: asthma was induced in wild type (WT) and CerS2 null mice with ovalbumin (OVA), and inflammatory cytokines and CD4 (cluster of differentiation 4)+ T helper (Th) cell profiles were analyzed. We also compared the functional capacity of CD4+ T cells isolated from WT and CerS2 null mice. (3) Results: CerS2 null mice exhibited milder symptoms and lower Th2 responses than WT mice after OVA exposure. CerS2 null CD4+ T cells showed impaired Th2 and increased Th17 responses with concomitant higher T cell receptor (TCR) signal strength after TCR stimulation. Notably, increased Th17 responses of CerS2 null CD4+ T cells appeared only in TCR-mediated, but not in TCR-independent, treatment. (4) Conclusions: altered Th2/Th17 immune response with higher TCR signal strength was observed in CerS2 null CD4+ T cells upon TCR stimulation. CerS2 and very-long chain SLs may be therapeutic targets for Th2-related diseases such as asthma.

scholarly journals Functional Uncoupling of T-cell Receptor Engagement and Lck Activation in Anergic Human Thymic CD4+T Cells

2001 ◽  
Vol 276 (20) ◽  
pp. 17455-17460 ◽  
Author(s):  
Wakae Fujimaki ◽  
Makio Iwashima ◽  
Junji Yagi ◽  
Hua Zhang ◽  
Hisako Yagi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor

scholarly journals Alteration of Interleukin 4 Production Results in the Inhibition of T Helper Type 2 Cell–Dominated Inflammatory Bowel Disease in T Cell Receptor α Chain–Deficient Mice

1999 ◽  
Vol 190 (5) ◽  
pp. 607-616 ◽  
Author(s):  
Hideki Iijima ◽  
Ichiro Takahashi ◽  
Daisuke Kishi ◽  
Jin-Kyung Kim ◽  
Sunao Kawano ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Bowel Disease ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
T Helper ◽  
Inflammatory Bowel ◽  
Α Chain

T cell receptor α chain–deficient (TCR-α−/−) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4+TCR-ββ (CD4+ββ) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4+ββ T cells, we treated TCR-α−/− mice with anti–IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-α−/− mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti–IL-4 mAb–treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab–treated mice. Although TCR-α−/− mice treated with either specific or mock Ab developed CD4+ββ T cells, only those treated with anti–IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon γ–specific expression. These findings suggest that IL-4–producing Th2-type CD4+ββ T cells play a major immunopathological role in the induction of IBD in TCR-α−/− mice, a role that anti–IL-4 mAb inhibits by causing Th2-type CD4+ββ T cells to shift to the Th1 type.

scholarly journals CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer

2002 ◽  
Vol 196 (4) ◽  
pp. 481-492 ◽  
Author(s):  
Kristin V. Tarbell ◽  
Mark Lee ◽  
Erik Ranheim ◽  
Cheng Chi Chao ◽  
Maija Sanna ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Glutamic Acid Decarboxylase ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Acid Decarboxylase ◽  
Gad 65

Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286–300 (p286) of GAD65. These mice have GAD65-specific CD4+ T cells, as shown by staining with an I-Ag7(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α, and IL-10 when stimulated in vitro with GAD65 peptide 286–300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4+ T cells, or p286-tetramer+CD4+ Tcells, from GAD65 286–300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286–300-specific T cells have disease protective capacity and are not pathogenic.

T-CELL RECEPTOR INDEPENDENT ACTIVATION OF CD4+T-CELLS IN SEVERE ACUTE PANCREATITIS

Pancreas ◽  
2008 ◽  
Vol 37 (4) ◽  
pp. 468
Author(s):  
A. Dummer ◽  
M. Sendler ◽  
F.-U. Weiss ◽  
B. M. Bröker ◽  
M. M. Lerch ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Pancreatitis ◽  
T Cell ◽  
T Cell Receptor ◽  
Severe Acute Pancreatitis ◽  
Cd4 T Cells ◽  
Cell Receptor
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