scholarly journals Cbp Deficiency Alters Csk Localization in Lipid Rafts but Does Not Affect T-Cell Development

2005 ◽  
Vol 25 (19) ◽  
pp. 8486-8495 ◽  
Author(s):  
Shengli Xu ◽  
Jianxin Huo ◽  
Joy En-Lin Tan ◽  
Kong-Peng Lam
Keyword(s):  
T Cell ◽  
Lipid Rafts ◽  
Tyrosine Kinases ◽  
Germ Line ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Calcium Flux ◽  
Functional Defect ◽  
Deficient Mice

ABSTRACT The ubiquitously expressed transmembrane adaptor Csk-binding protein (Cbp) recruits Csk to lipid rafts, where the latter exerts its negative regulatory effect on the Src family of protein tyrosine kinases. We have inactivated Cbp in the mouse germ line. In contrast to Csk gene inactivation, which leads to embryonic lethality and impaired T-cell development, Cbp-deficient mice were viable and exhibited normal T-cell development but with an increased thymocyte population. In the absence of Cbp, the amount of Csk that localizes to the lipid rafts was greatly reduced. Interestingly, this altered lipid raft localization of Csk did not lead to any detectable biochemical or functional defect in T cells. The T-cell receptor-induced intracellular calcium flux, cell proliferation, and cytokine secretion were not affected by the absence of Cbp. Peripheral T-cell tolerance to superantigen SEB was also largely intact in Cbp-deficient mice. Thus, Cbp is dispensable for T-cell development and activation.

scholarly journals Inactivation of c-Cbl Reverses Neonatal Lethality and T Cell Developmental Arrest of SLP-76–deficient Mice

2004 ◽  
Vol 200 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Y. Jeffrey Chiang ◽  
Connie L. Sommers ◽  
Martha S. Jordan ◽  
Hua Gu ◽  
Lawrence E. Samelson ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Adaptor Protein ◽  
Premature Death ◽  
Cell Receptor ◽  
Cell Development ◽  
Neonatal Lethality ◽  
Deficient Mice

c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76–deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76–deficient mice and partially reversed the T cell development arrest in these mice. SLP-76−/− Cbl−/− mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4+ T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2−/− SLP-76−/− Cbl−/− triple knockout mice. Analysis of the signal transduction properties of SLP-76−/− Cbl−/− T cells reveals a novel SLP-76– and linker for activation of T cells–independent pathway of extracellular signal–regulated kinase activation, which is normally down-regulated by c-Cbl.

scholarly journals Signal-Transducing Adaptor Molecules STAM1 and STAM2 Are Required for T-Cell Development and Survival

2002 ◽  
Vol 22 (24) ◽  
pp. 8648-8658 ◽  
Author(s):  
Mitsuhiro Yamada ◽  
Naoto Ishii ◽  
Hironobu Asao ◽  
Kazuko Murata ◽  
Chieko Kanazawa ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Double Mutant ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cell Development ◽  
Mitogen Activated Protein Kinase ◽  
Calcium Flux ◽  
Mitogen Activated Protein

ABSTRACT We previously reported that the STAM family members STAM1 and STAM2 are phosphorylated on tyrosine upon stimulation with cytokines through the γc-Jak3 signaling pathway, which is essential for T-cell development. Mice with targeted mutations in either STAM1 or STAM2 show no abnormality in T-cell development, and mice with double mutations for STAM1 and STAM2 are embryonically lethal; therefore, here we generated mice with T-cell-specific double mutations for STAM1 and STAM2 using the Cre/loxP system. These STAM1−/− STAM2−/− mice showed a significant reduction in thymocytes and a profound reduction in peripheral mature T cells. In proliferation assays, thymocytes derived from the double mutant mice showed a defective response to T-cell-receptor (TCR) stimulation by antibodies and/or cytokines, interleukin-2 (IL-2) and IL-7. However, signaling events downstream of receptors for IL-2 and IL-7, such as activations of STAT5, extracellular signal-regulated kinase (ERK), and protein kinase B (PKB)/Akt, and c-myc induction, were normal in the double mutant thymocytes. Upon TCR-mediated stimulation, prolonged activations of p38 mitogen-activated protein kinase and Jun N-terminal protein kinase were seen, but activations of ERK, PKB/Akt, and intracellular calcium flux were normal in the double mutant thymocytes. When the cell viability of cultured thymocytes was assessed, the double mutant thymocytes died more quickly than controls. These results demonstrate that the STAMs are indispensably involved in T-cell development and survival in the thymus through the prevention of apoptosis but are dispensable for the proximal signaling of TCR and cytokine receptors.

scholarly journals Pim1 Reconstitutes Thymus Cellularity in Interleukin 7–And Common γ Chain–Mutant Mice and Permits Thymocyte Maturation in Rag- but Not Cd3γ-Deficient Mice

1999 ◽  
Vol 190 (8) ◽  
pp. 1059-1068 ◽  
Author(s):  
Heinz Jacobs ◽  
Paul Krimpenfort ◽  
Mariëlle Haks ◽  
John Allen ◽  
Bianca Blom ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Interleukin 7 ◽  
Tcr Signal Transduction ◽  
Slow Expansion ◽  
Deficient Mice

The majority of lymphomas induced in Rag-deficient mice by Moloney murine leukemia virus (MoMuLV) infection express the CD4 and/or CD8 markers, indicating that proviral insertions cause activation of genes affecting the development from CD4−8− pro-T cells into CD4+8+ pre-T cells. Similar to MoMuLV wild-type tumors, 50% of CD4+8+ Rag-deficient tumors carry a provirus near the Pim1 protooncogene. To study the function of PIM proteins in T cell development in a more controlled setting, a Pim1 transgene was crossed into mice deficient in either cytokine or T cell receptor (TCR) signal transduction pathways. Pim1 reconstitutes thymic cellularity in interleukin (IL)-7– and common γ chain–deficient mice. In Pim1-transgenic Rag-deficient mice but notably not in CD3γ-deficient mice, we observed slow expansion of the CD4+8+ thymic compartment to almost normal size. Based on these results, we propose that PIM1 functions as an efficient effector of the IL-7 pathway, thereby enabling Rag-deficient pro-T cells to bypass the pre-TCR–controlled checkpoint in T cell development.

CD4+CD25+ T-cell development is regulated by at least 2 distinct mechanisms

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 555-560 ◽  
Author(s):  
Akira Suto ◽  
Hiroshi Nakajima ◽  
Kei Ikeda ◽  
Shuichi Kubo ◽  
Toshinori Nakayama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Histocompatibility Complex ◽  
Organ Specific ◽  
Immunoregulatory T Cells ◽  
Deficient Mice

Abstract It has recently been shown that CD4+CD25+ T cells are immunoregulatory T cells that prevent CD4+ T-cell–mediated organ-specific autoimmune diseases. In this study, the regulatory mechanism of CD4+CD25+ T-cell development were investigated using T-cell receptor (TCR) transgenic mice. It was found that CD4+CD25+ T cells preferentially expressed the endogenous TCRα chain in DO10+ TCR transgenic mice compared with CD4+CD25− T cells. Moreover, it was found that CD4+CD25+ thymocytes were severely decreased in DO10+ TCR-α−/− mice in positively selecting and negatively selecting backgrounds, whereas CD4+CD25− thymocytes efficiently developed by transgenic TCR in DO10+ TCR-α−/− mice in positively selecting backgrounds, indicating that the appropriate affinity of TCR to major histocompatibility complex (MHC) for the development of CD4+CD25+ thymocytes is different from that of CD4+CD25− thymocytes and that a certain TCR–MHC affinity is required for the development of CD4+CD25+ thymocytes. Finally, it was found that, in contrast to thymus, CD4+CD25+ T cells were readily detected in spleen of DO10+TCR-α−/− mice in positively selecting backgrounds and that splenic CD4+CD25+ T cells, but not CD4+CD25+ thymocytes, were significantly decreased in B-cell–deficient mice, suggesting that B cells may control the peripheral pool of CD4+CD25+ T cells. Together, these results indicate that the development of CD4+CD25+ T cells in thymus and the homeostasis of CD4+CD25+ T cells in periphery are regulated by distinct mechanisms.

scholarly journals Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies

2007 ◽  
Vol 204 (11) ◽  
pp. 2537-2544 ◽  
Author(s):  
Gabrielle M. Siegers ◽  
Mahima Swamy ◽  
Edgar Fernández-Malavé ◽  
Susana Minguet ◽  
Sylvia Rathmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Cell Development ◽  
Γδ T Cell ◽  
Deficient Mice ◽  
Γδ T Cell Receptor

The γδ T cell receptor for antigen (TCR) comprises the clonotypic TCRγδ, the CD3 (CD3γε and/or CD3δε), and the ζζ dimers. γδ T cells do not develop in CD3γ-deficient mice, whereas human patients lacking CD3γ have abundant peripheral blood γδ T cells expressing high γδ TCR levels. In an attempt to identify the molecular basis for these discordant phenotypes, we determined the stoichiometries of mouse and human γδ TCRs using blue native polyacrylamide gel electrophoresis and anti-TCR–specific antibodies. The γδ TCR isolated in digitonin from primary and cultured human γδ T cells includes CD3δ, with a TCRγδCD3ε2δγζ2 stoichiometry. In CD3γ-deficient patients, this may allow substitution of CD3γ by the CD3δ chain and thereby support γδ T cell development. In contrast, the mouse γδ TCR does not incorporate CD3δ and has a TCRγδCD3ε2γ2ζ2 stoichiometry. CD3γ-deficient mice exhibit a block in γδ T cell development. A human, but not a mouse, CD3δ transgene rescues γδ T cell development in mice lacking both mouse CD3δ and CD3γ chains. This suggests important structural and/or functional differences between human and mouse CD3δ chains during γδ T cell development. Collectively, our results indicate that the different γδ T cell phenotypes between CD3γ-deficient humans and mice can be explained by differences in their γδ TCR composition.

scholarly journals Deletion of the mouse T-cell receptor beta gene enhancer blocks alphabeta T-cell development.

1996 ◽  
Vol 93 (15) ◽  
pp. 7877-7881 ◽  
Author(s):  
G. Bouvier ◽  
F. Watrin ◽  
M. Naspetti ◽  
C. Verthuy ◽  
P. Naquet ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Gene Enhancer ◽  
T Cell Receptor Beta ◽  
Beta Gene ◽  
Receptor Beta

Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice

Nature ◽  
1994 ◽  
Vol 372 (6506) ◽  
pp. 560-563 ◽  
Author(s):  
Sharon L. Erickson ◽  
Frederic J. de Sauvage ◽  
Kristine Kikly ◽  
Karen Carver-Moore ◽  
Sharon Pitts-Meek ◽  
...  
Keyword(s):  
T Cell ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
T Cell Development ◽  
Cell Development ◽  
Tnf Receptor ◽  
Deficient Mice ◽  
Necrosis Factor

scholarly journals Blockade of transgenic gamma delta T cell development in beta 2-microglobulin deficient mice.

1992 ◽  
Vol 11 (1) ◽  
pp. 25-31 ◽  
Author(s):  
P. Pereira ◽  
M. Zijlstra ◽  
J. McMaster ◽  
J.M. Loring ◽  
R. Jaenisch ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Gamma Delta ◽  
Beta 2 ◽  
Beta 2 Microglobulin ◽  
Gamma Delta T Cell ◽  
Deficient Mice

Loss of Function of the Homeobox Gene Hoxa-9 Perturbs Early T-Cell Development and Induces Apoptosis in Primitive Thymocytes

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 383-393 ◽  
Author(s):  
David J. Izon ◽  
Sofia Rozenfeld ◽  
Stephen T. Fong ◽  
László Kömüves ◽  
Corey Largman ◽  
...  
Keyword(s):  
T Cell ◽  
Hox Genes ◽  
Apoptotic Cell ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Homeobox Gene ◽  
Cell Receptor ◽  
Cell Development ◽  
Loss Of Function ◽  
Double Positive

Abstract Hox homeobox genes play a crucial role in specifying the embryonic body pattern. However, a role for Hox genes in T-cell development has not been explored. The Hoxa-9 gene is expressed in normal adult and fetal thymuses. Fetal thymuses of mice homozygous for an interruption of the Hoxa-9 gene are one eighth normal size and have a 25-fold decrease in the number of primitive thymocytes expressing the interleukin-2 receptor (IL-2R, CD25). Progression to the double positive (CD4+CD8+) stage is dramatically retarded in fetal thymic organ cultures. This aberrant development is associated with decreased amounts of intracellular CD3 and T-cell receptor β (TCRβ) and reduced surface expression of IL-7R and E-cadherin. Mutant thymocytes show a significant increase in apoptotic cell death and premature downregulation of bcl-2 expression. A similar phenotype is seen in primitive thymocytes from adult Hoxa-9−/− mice and from mice transplanted with Hoxa-9−/−marrow. Hoxa-9 appears to play a previously unsuspected role in T-cell ontogeny by modulating cell survival of early thymocytes and by regulating their subsequent differentiation.

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