Interleukin 4 expressed in situ selectively alters thymocyte development.

Lewis, David B.; Yu, Chenchen; Forbush, Katherine A.; Carpenter, Jeffery H.; Sato, Timothy A.; Grossman, A. R.; Liggitt, Denny; Perlmutter, Roger M.

doi:10.1084/jem.173.1.89

Cited by 78 publications

(38 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Constructs using the insulin promoter may direct expression of the transgene not only to pancreatic J3 cells but also to the thymus (24,25). Furthermore, it has been shown that IL-4, when selectively overexpressed in the thymus oftransgenic mice, significantly alters thymocyte development and thymus architecture (19). To address possible transgene expression in the thymus of NOD-IL-4 mice, IL-4 levels in supernatants from thymocytes after short-term in vitro culture were determined using an ELISA assay.…”

Section: Resultsmentioning

confidence: 99%

“…Thymocytes from three NOD-IL-4 mice and three nontransgenic littermates were cultured (5 X 106/ml) in RPMI 1640 supplemented with 1 mM NaPyruvate, 2 mM L-glutamine, 0.05 mM 2-ME, 100 U/ml penicillin, 100 ~g/ml streptomycin, and 10% FCS for 24 h (19). Supernatants from islet cells and thymocytes were removed, and IL-4 levels were determined with an ELISA assay using mAb BVD4-1D 11 and biotinylated Ab 11B 11 as capture and detection Abs, respectively (PharMingen, San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice.

Mueller

Krahl

Sarvetnick

1996

The Journal of Experimental Medicine

291

143

View full text Add to dashboard Cite

SummaryDiabetes in nonobese diabetic (NOD) mice is a T cell-dependent autoimmune disease. The destructive activities of autoreactive T cells have been shown to be tightly regulated by effector molecules. In particular, T helper (Th) 1 cytokines have been linked to diabetes pathogenesis, whereas Th2 cytokines and the cells that release them have been postulated to be protective from disease. To test this hypothesis, we generated transgenic NOD mice that express interleukin (IL) 4 in their pancreatic [3 cells under the control of the human insulin promoter. We found that transgenic NOD-IL-4 mice, both females and males, were completely protected from insulitis and diabetes. Induction of functional tolerance to islet antigens in these mice was indicated by their inability to reject syngeneic pancreatic islets and the failure of diabetogenic spleen cells to induce diabetes in transgenic NOD-IL-4 recipients. Interestingly, however, islet expression of IL-4 was incapable of preventing islet rejection in overfly diabetic NOD recipient mice. These results demonstrate that the Th2 cytokine IL-4 can prevent the development of autoimmunity and destructive autoreactivity in the NOD mouse. Its ability to regulate the disease process in the periphery also indicates that autoimmune diabetes in NOD mice is not a systemic disease, and it can be modulated from the islet compartment.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice.

Mueller

Krahl

Sarvetnick

1996

The Journal of Experimental Medicine

291

143

View full text Add to dashboard Cite

show abstract

“…There are both similarities and differences between transgenic Stat6VT mice and transgenic mice overexpressing IL-4 (15,39,69). Transgenic IL-4 had dramatic effects on thymic cellularity and thymocyte maturation, suggesting that an active Stat6 does not mimic all effects of transgenic IL-4 expression.…”

Section: Discussionmentioning

confidence: 99%

Expression of a Constitutively Active Stat6 In Vivo Alters Lymphocyte Homeostasis with Distinct Effects in T and B Cells

Bruns

Schindler²,

Kaplan

2003

The Journal of Immunology

View full text Add to dashboard Cite

IL-4 is a critical cytokine in the regulation of immune responses and genesis of atopy. Engagement of the IL-4R activates multiple signaling pathways, including the transcription factor Stat6. Stat6-deficient mice demonstrate the importance of this factor in lymphocyte proliferation, gene expression, and Th cell differentiation. Recently, a mutant Stat6 (Stat6VT) was generated that is transcriptionally active independent of IL-4 stimulation. To determine the ability of a constitutively active Stat6 to mimic IL-4-stimulated responses, we have generated transgenic mice expressing Stat6VT under control of the CD2 locus control region, restricting expression to lymphoid populations. The phenotype of Stat6VT transgenic mice is similar, but not identical, to IL-4 transgenic mice, suggesting a critical role for Stat6-independent signaling pathways in the generation of some IL-4 responses in vivo. The expression of a constitutively active Stat6 in vivo increases surface expression of IL-4-induced genes and increases serum levels of IgG1 and IgE, compared with nontransgenic mice. Stat6VT expression increases Th2 differentiation in vivo and in vitro. Stat6VT expression also dramatically alters homeostasis of peripheral lymphocyte populations resulting in decreased CD3+ cells and increased B220+ cells, compared with nontransgenic littermates. Altered T and B cell populations correlate with an activated phenotype and increased cell death in transgenic T cell, but not B cell, populations. Together these results suggest that expression of a constitutively active Stat6 has distinct effects on B and T lymphocytes.

show abstract

“…The LCK-PLZF transgene was constructed by inserting the ∼2KB gene into the LCK vector as described (23). Transgene DNA was injected into fertilized C57BL/6 eggs by the Memorial Sloan-Kettering Cancer Center (MSKCC) Mouse Genetics Core Facility.…”

Section: Micementioning

confidence: 99%

PLZF Induces the Spontaneous Acquisition of Memory/Effector Functions in T Cells Independently of NKT Cell-Related Signals

Kovalovsky

Alonzo

Uche

et al. 2010

The Journal of Immunology

102

View full text Add to dashboard Cite

The broad complex, tramtrack, bric-a-brac–zinc finger (BTB-ZF) transcription factor promyelocytic leukemia zinc finger (PLZF) is required for development of the characteristic innate/effector functions of NKT cells. In this study, we report the characterization and functional analysis of transgenic mouse T cells with forced expression of PLZF. PLZF expression was sufficient to provide some memory/effector functions to T cells without the need for Ag stimulation or proliferation. The acquisition of this phenotype did not require the proliferation typically associated with T cell activation. Furthermore, PLZF transgenic cells maintained a diverse TCR repertoire, indicating that there was no preferential expansion of specific clones. Functionally, PLZF transgenic CD4 and CD8 lymphocytes were similar to wild type memory cells, in that they had similar requirements for costimulation and exhibited a similar pattern of cytokine secretion, with the notable exception that transgenic T cells produced significantly increased levels of IL-17. Whereas transgene-mediated PLZF expression was not sufficient to rescue NKT cell development in Fyn- or signaling lymphocytic activation-associated protein (SAP)-deficient mice, the acquisition of memory/effector functions induced by PLZF in conventional T cells was independent of Fyn and SAP. These data show that PLZF is sufficient to promote T cell effector functions and that PLZF acts independently of SAP- and Fyn-mediated signaling pathways.

show abstract

Interleukin 4 expressed in situ selectively alters thymocyte development.

Cited by 78 publications

References 67 publications

Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice.

Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice.

Expression of a Constitutively Active Stat6 In Vivo Alters Lymphocyte Homeostasis with Distinct Effects in T and B Cells

PLZF Induces the Spontaneous Acquisition of Memory/Effector Functions in T Cells Independently of NKT Cell-Related Signals

Contact Info

Product

Resources

About