Cross-linking of T-cell receptors on double-positive thymocytes induces a cytokine-mediated stromal activation process linked to cell death.

Lerner, Adam; Clayton, Linda K.; Mizoguchi, Emiko; Ghendler, Yoseph; Ewijk, Willem van; Koyasu, Shigeo; Bhan, Atul K.; Reinherz, Ellis L.

doi:10.1002/j.1460-2075.1996.tb00974.x

Cited by 47 publications

(23 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the high level of UBP43 expression in the thymus suggest a possible link between UBP43 and immature T-cell apoptosis. Therefore, we also analyzed UBP43 expression in a mouse model with regulated thymocyte apoptosis (28). There were no observed changes in UBP43 expression in thymic RNA derived from either untreated mice or mice treated with anti-CD3 ε monoclonal antibody to induce thymocyte apoptosis (data not shown).…”

Section: Discussionmentioning

confidence: 99%

A Novel Ubiquitin-Specific Protease, UBP43, Cloned from Leukemia Fusion Protein AML1-ETO-Expressing Mice, Functions in Hematopoietic Cell Differentiation

Liu

Ilaria

Kingsley

et al. 1999

Molecular and Cellular Biology

142

129

View full text Add to dashboard Cite

Using PCR-coupled subtractive screening-representational difference analysis, we have cloned a novel gene from AML1-ETO knockin mice. This gene is highly expressed in the yolk sac and fetal liver of the knockin mice. Nucleotide sequence analysis indicates that its cDNA contains an 1,107-bp open reading frame encoding a 368-amino-acid polypeptide. Further protein sequence and protein translation analysis shows that it belongs to a family of ubiquitin-specific proteases (UBP), and its molecular mass is 43 kDa. Therefore, we have named this gene UBP43. Like other ubiquitin proteases, the UBP43 protein has deubiquitinating enzyme activity. Protein ubiquitination has been implicated in many important cellular events. In wild-type adult mice, UBP43 is highly expressed in the thymus and in peritoneal macrophages. Among nine different murine hematopoietic cell lines analyzed, UBP43 expression is detectable only in cell lines related to the monocytic lineage. Furthermore, its expression is regulated during cytokine-induced monocytic cell differentiation. We have investigated its function in the hematopoietic myeloid cell line M1. UBP43 was introduced into M1 cells by retroviral gene transfer, and several high-expressing UBP43 clones were obtained for further study. Morphologic and cell surface marker examination of UBP43/M1 cells reveals that overexpression of UBP43 blocks cytokine-induced terminal differentiation of monocytic cells. These data suggest that UBP43 plays an important role in hematopoiesis by modulating either the ubiquitin-dependent proteolytic pathway or the ubiquitination state of another regulatory factor(s) during myeloid cell differentiation. t(8;21) is associated with 15% of de novo acute myelogenous leukemia cases and creates the AML1-ETO fusion protein. AML1-ETO knockin mice have been generated to study the effect of the leukemia-associated fusion protein AML1-ETO on hematopoiesis and the pathogenesis of leukemia (34, 53).

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel Ubiquitin-Specific Protease, UBP43, Cloned from Leukemia Fusion Protein AML1-ETO-Expressing Mice, Functions in Hematopoietic Cell Differentiation

Liu

Ilaria

Kingsley

et al. 1999

Molecular and Cellular Biology

142

129

View full text Add to dashboard Cite

show abstract

“…anti-CD3 Ab, a phenomenon that is probably related to autoAginduced negative selection during T cell maturation (52)(53)(54)(55)(56)(57). Previously, it was noted that the CD4 ϩ CD8 ϩ thymocytes isolated from the transgenic mice that expressed a DNI-B␣ protein in T cells were protected from anti-CD3-induced apoptosis (37).…”

Section: Cd4mentioning

confidence: 99%

I-κB Kinases α and β Have Distinct Roles in Regulating Murine T Cell Function

Ren

Schmalstieg²,

Oers

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

NF-κB is a transcription factor that regulates a variety of genes involved in the control of the immune and inflammatory responses. Activation of NF-κB is mediated by an inducible I-κB kinase (IKK) complex comprised of two catalytic subunits, IKKα and IKKβ. In this study, the role of these kinases in the development and function of T lymphocytes was explored using transgenic mice expressing the dominant-negative forms of one or both kinases under the control of a T cell-specific promoter. Activation of the NF-κB pathway in thymocytes isolated from these transgenic mice following treatment with either PMA and ionomycin or anti-CD3 was markedly inhibited. Although inhibition of IKKα and/or IKKβ function did not alter T cell development in these transgenic mice, the proliferative response to anti-CD3 was reduced in thymocytes isolated from mice expressing dominant-negative IKKβ. However, inhibition of both IKKα and IKKβ was required to markedly reduce cytokine production in thymocytes isolated from these transgenic mice. Finally, we demonstrated that IKKα and IKKβ have opposite roles on the regulation of anti-CD3-induced apoptosis of double-positive thymocytes. These results suggest that IKKα and IKKβ have distinct roles in regulating thymocyte function.

show abstract

“…Crosslinking of TCRs on DP thymocytes induces the production of various cytokines (14) and numerous studies have shown that cytokines such as IL-7 and IL-2 can profoundly affect thymocyte growth and survival (15). However, the precise role of IL-2/IL-2R signaling in thymocyte development remains controversial due to apparently contradictory studies providing evidence for both the promotion and inhibition of thymocyte growth by this signaling pathway (16).…”

Section: Cd4mentioning

confidence: 99%

A Requirement for IL-2/IL-2 Receptor Signaling in Intrathymic Negative Selection

Bassiri

Carding

2001

The Journal of Immunology

View full text Add to dashboard Cite

The nature of the signals that influence thymocyte selection and determine the fate of CD4+8+ (double positive) thymocytes remains unclear. Cytokines produced locally in the thymus may modulate signals delivered by TCR-MHC/peptide interactions and thereby influence the fate of double-positive thymocytes. Because the IL-2/IL-2R signaling pathway has been implicated in thymocyte and peripheral T cell survival, we investigated the possibility that IL-2/IL-2R interactions contribute to the deletion of self-reactive, Ag-specific thymocytes. By using nontransgenic and transgenic IL-2-sufficient and -deficient animal model systems, we have shown that during TCR-mediated thymocyte apoptosis, IL-2 protein is expressed in situ in the thymus, and apoptotic thymocytes up-regulate expression of IL-2Rs. IL-2R+ double-positive and CD4 single-positive thymocytes undergoing activation-induced cell death bind and internalize IL-2. IL-2-deficient thymocytes are resistant to TCR/CD3-mediated apoptotic death, which is overcome by providing exogenous IL-2 to IL-2−/− mice. Furthermore, disruption or blockade of IL-2/IL-2R interactions in vivo during Ag-mediated selection rescues some MHC class II-restricted thymocytes from apoptosis. Collectively, these findings provide evidence for the direct involvement of the IL-2/IL-2R signaling pathway in the deletion of Ag-specific thymocyte populations and suggest that CD4 T cell hyperplasia and autoimmunity in IL-2−/− mice is a consequence of ineffective deletion of self-reactive T cells.

show abstract

Cross-linking of T-cell receptors on double-positive thymocytes induces a cytokine-mediated stromal activation process linked to cell death.

Cited by 47 publications

References 65 publications

A Novel Ubiquitin-Specific Protease, UBP43, Cloned from Leukemia Fusion Protein AML1-ETO-Expressing Mice, Functions in Hematopoietic Cell Differentiation

A Novel Ubiquitin-Specific Protease, UBP43, Cloned from Leukemia Fusion Protein AML1-ETO-Expressing Mice, Functions in Hematopoietic Cell Differentiation

I-κB Kinases α and β Have Distinct Roles in Regulating Murine T Cell Function

A Requirement for IL-2/IL-2 Receptor Signaling in Intrathymic Negative Selection

Contact Info

Product

Resources

About