Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting

Nature ◽  
1991 ◽  
Vol 352 (6336) ◽  
pp. 621-624 ◽  
Author(s):  
Hubert Schorle ◽  
Thomas Holtschke ◽  
Thomas Hünig ◽  
Anneliese Schimpl ◽  
Ivan Horak
Keyword(s):  
T Cells ◽  
Gene Targeting ◽  
Interleukin 2 ◽  
And Function

Interleukin-2 Receptor Subunit Expression and Function on Human Peripheral T Cells Is Not Dependent on the Anticoagulant

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2989-2993 ◽  
Author(s):  
Guido L. Vanham ◽  
Godelieve Penne ◽  
Chris Vereecken ◽  
Johan Vingerhoets ◽  
Luc Kestens
Keyword(s):  
T Cells ◽  
Interleukin 2 ◽  
Receptor Subunit ◽  
Interleukin 2 Receptor ◽  
Peripheral T Cells ◽  
Subunit Expression ◽  
And Function

scholarly journals IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2409-2414 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Steven A. Rosenberg
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
High Dose ◽  
Protein Levels ◽  
And Function ◽  
The Impact

Abstract Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

scholarly journals Aberrant Contraction of Antigen-Specific CD4 T Cells after Infection in the Absence of Gamma Interferon or Its Receptor

2006 ◽  
Vol 74 (11) ◽  
pp. 6252-6263 ◽  
Author(s):  
Jodie S. Haring ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Model Systems ◽  
Important Regulator ◽  
Ifn Γ ◽  
And Function ◽  
Deficient Mice

ABSTRACT Several lines of evidence from different model systems suggest that gamma interferon (IFN-γ) is an important regulator of T-cell contraction after antigen (Ag)-driven expansion. To specifically investigate the role of IFN-γ in regulating the contraction of Ag-specific CD4 T cells, we infected IFN-γ−/− and IFN-γR1−/− mice with attenuated Listeria monocytogenes and monitored the numbers of Ag-specific CD4 T cells during the expansion, contraction, and memory phases of the immune response to infection. In the absence of IFN-γ or the ligand-binding portion of its receptor, Ag-specific CD4 T cells exhibited normal expansion in numbers, but in both strains of deficient mice there was very little decrease in the number of Ag-specific CD4 T cells even at time points later than day 90 after infection. This significant delay in contraction was not due to prolonged infection, since mice treated with antibiotics to conclusively eliminate infection exhibited the same defect in contraction. In addition to altering the number of Ag-specific CD4 T cells, the absence of IFN-γ signaling also changed the phenotype of cells generated after infection. IFN-γR1−/− Ag-specific CD4 T cells reacquired expression of CD127 more quickly than wild-type cells, and more IFN-γR1−/− CD4 T cells were capable of producing both IFN-γ and interleukin 2 following Ag stimulation. From these data we conclude that IFN-γ regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection.

Interleukin-2 Receptor Subunit Expression and Function on Human Peripheral T Cells Is Not Dependent on the Anticoagulant

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2989-2993
Author(s):  
Guido L. Vanham ◽  
Godelieve Penne ◽  
Chris Vereecken ◽  
Johan Vingerhoets ◽  
Luc Kestens
Keyword(s):  
T Cells ◽  
Interleukin 2 ◽  
Receptor Subunit ◽  
Interleukin 2 Receptor ◽  
Peripheral T Cells ◽  
Subunit Expression ◽  
And Function

Low-dose Interleukin-2 in the Treatment of Autoimmune Disease

2014 ◽  
Vol 10 (02) ◽  
pp. 157 ◽  
Author(s):  
John Koreth ◽  
Jerome Ritz ◽  
George C Tsokos ◽  
Alberto Pugliese ◽  
Thomas R Malek ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Diseases ◽  
Lupus Erythematosus ◽  
Low Dose ◽  
Cell Function ◽  
Interleukin 2 ◽  
The Us ◽  
High Doses ◽  
And Function ◽  
Preclinical And Clinical Studies

CD4+ regulatory T cells (Tregs) act to maintain peripheral immune tolerance. Decreased numbers or defective function of Tregs has been implicated in the pathogenesis of various autoimmune diseases. Interleukin-2 (IL-2) at high doses is approved by the US Food and Drug Administration (FDA) as an immune stimulant to induce anti-tumor cytotoxicity. However, at physiologic doses, IL-2 is necessary for the expansion and function of Tregs. Treatment with low-dose IL-2 can selectively enhance Treg function while avoiding the activation of effector T cells and ameliorate immune inflammation. Administration of low doses of IL-2 to patients suffering from chronic graft versus host disease (cGvHD) or chronic hepatitis C-mediated vasculitis resulted in significant clinical benefit, which was linked to improved Treg cell function. Preclinical studies suggest that low-dose IL-2 may offer benefit in other autoimmune diseases including systemic lupus erythematosus and type 1 diabetes. Ongoing preclinical and clinical studies indicate a wider potential role for low-dose IL-2 based Treg therapeutics in human autoimmune diseases.

scholarly journals Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity

2019 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Autoimmune Response ◽  
Wild Type ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Receptor Component ◽  
And Function

AbstractInterleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response.One Sentence SummaryA CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.

scholarly journals An IL-2 mutein engineered to promote expansion of regulatory T cells arrests ongoing autoimmunity in mice

2020 ◽  
Vol 5 (50) ◽  
pp. eaba5264 ◽  
Author(s):  
Liliane Khoryati ◽  
Minh Nguyet Pham ◽  
McKenna Sherve ◽  
Swarnima Kumari ◽  
Kevin Cook ◽  
...  
Keyword(s):  
T Cells ◽  
Dose Range ◽  
Interleukin 2 ◽  
Nod Mice ◽  
Effector Cells ◽  
Inflammatory Conditions ◽  
Cell Selectivity ◽  
Receptor Component ◽  
Cell Enrichment ◽  
And Function

Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T (Treg) cells, and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2–based therapeutics with improved Treg cell specificity. From a panel of rationally designed murine IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg cell selectivity due to increased dependence on the IL-2 receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg cell enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg cell growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared with Fc-fused wild-type IL-2. Preferential Treg cell enrichment was also observed in the presence of activated pathogenic T cells in the pancreas of nonobese diabetic (NOD) mice, despite a loss of Treg cell selectivity in an IL-2R proximal response. These properties facilitated potent and extended resolution of NOD diabetes with infrequent dosing schedules.

scholarly journals ROG Negatively Regulates T-Cell Activation but Is Dispensable for Th-Cell Differentiation

2005 ◽  
Vol 25 (2) ◽  
pp. 554-562 ◽  
Author(s):  
Bok Yun Kang ◽  
Shi-Chuen Miaw ◽  
I-Cheng Ho
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Target Gene ◽  
Interleukin 2 ◽  
Negative Regulator ◽  
Th2 Cells ◽  
Th Cells ◽  
And Function

ABSTRACT ROG, a transcriptional repressor, is a direct target gene of NF-AT and a putative negative regulator of T-cell activation. In addition, overexpression of ROG suppresses the activity of GATA-3, implying a role of ROG in the differentiation and function of Th cells. Despite these observations, the function of ROG has yet to be confirmed by loss-of-function approaches. Here we report that ROG-deficient T cells are hypersensitive to anti-CD3 stimulation and produce more interleukin-2 (IL-2) due to enhanced NF-κB activity. ROG-deficient dendritic cells also produce more IL-12p40, another NF-κB target gene. However, ROG-deficient Th cells are capable of differentiating into Th1 and Th2 cells, and ROG-deficient mice have no defect in mounting appropriate Th immune responses in vivo. Thus, ROG is dispensable for the differentiation and function of Th cells but serves as a mediator of NF-AT-initiated suppression of NF-κB. Its mechanism of action and its expression pattern are distinct from those of other transcription factors negatively regulating the activation of T cells.

scholarly journals Spontaneous and glucocorticoid-induced apoptosis in human mature T lymphocytes

Blood ◽  
1995 ◽  
Vol 86 (11) ◽  
pp. 4199-4205 ◽  
Author(s):  
M Brunetti ◽  
N Martelli ◽  
A Colasante ◽  
M Piantelli ◽  
P Musiani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Number ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Cell Repertoire ◽  
Induced Apoptosis ◽  
And Function ◽  
Dose Dependent

Glucocorticoid (GC)-induced apoptosis is a well-recognized physiologic regulator of murine T-cell number and function. We have analyzed its mechanisms in human mature T cells, which have been thought to be insensitive until recently. Peripheral blood T cells showed sensitivity to GC-induced apoptosis soon after the proliferative response to a mitogenic stimulation, and were also sensitive to spontaneous (ie, growth factor deprivation-dependent) apoptosis. CD8+ T cells were more sensitive to both forms than CD4+ T cells. Acquisition of sensitivity to GC-induced apoptosis was not associated with any change in number or affinity of GC receptors. Both spontaneous and GC-induced apoptosis were increased by the macromolecular synthesis inhibitors, cycloheximide (CHX) and puromycin. A positive correlation between the degree of protein synthesis inhibition and the extent of apoptosis was observed. Interleukin-2 (IL-2) IL-4, and IL-10 protected (IL-2 > IL-10 > IL-4) T cells from both forms of apoptosis in a dose-dependent manner. Our data suggest that spontaneous and GC-induced apoptosis regulate the human mature T-cell repertoire by acting early after the immune response and differentially affecting T-cell subsets.

scholarly journals 3BP2 Deficiency Impairs the Response of B Cells, but Not T Cells, to Antigen Receptor Ligation

2006 ◽  
Vol 26 (14) ◽  
pp. 5214-5225 ◽  
Author(s):  
Miguel A. de la Fuente ◽  
Lalit Kumar ◽  
Bao Lu ◽  
Raif S. Geha
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Cycle Progression ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Normal Numbers ◽  
Tcr Signaling ◽  
And Function

ABSTRACT The adapter protein 3BP2 is expressed in lymphocytes; binds to Syk/ZAP-70, Vav, and phospholipase C-γ (PLC-γ); and is thought to be important for interleukin-2 gene transcription in T cells. To define the role of 3BP2 in lymphocyte development and function, we generated 3BP2-deficient mice. T-cell development, proliferation, cytokine secretion, and signaling in response to T-cell receptor (TCR) ligation were all normal in 3BP2−/− mice. 3BP2−/− mice had increased accumulation of pre-B cells in the bone marrow and a block in the progression of transitional B cells in the spleen from the T1 to the T2 stage, but normal numbers of mature B cells. B-cell proliferation, cell cycle progression, PLC-γ2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to B-cell receptor (BCR) ligation were all impaired. These results suggest that 3BP2 is important for BCR, but not for TCR signaling.

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