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 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 LAT-mediated signaling in CD4+CD25+ regulatory T cell development

2005 ◽  
Vol 203 (1) ◽  
pp. 119-129 ◽  
Author(s):  
Surapong Koonpaew ◽  
Shudan Shen ◽  
Lawrence Flowers ◽  
Weiguo Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
T Cell Development ◽  
Ectopic Expression ◽  
Adaptor Protein ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
Cell Development

Engagement of the T cell receptor for antigen (TCR) induces formation of signaling complexes mediated through the transmembrane adaptor protein, the linker for activation of T cells (LAT). LAT plays an important role in T cell development, activation, and homeostasis. A knock-in mutation at Tyr136, which is the phospholipase C (PLC)-γ1–binding site in LAT, leads to a severe autoimmune disease in mice. In this study, we show that CD4+CD25+ T reg cells that expressed Foxp3 transcription factor were nearly absent in both thymus and peripheral lymphoid organs of LATY136F mice. This defect was not a result of the autoimmune environment as LATY136F T reg cells also failed to develop in healthy LAT−/− mice that received mixed wild-type and LATY136F bone marrow cells. Moreover, adoptive transfer of normal CD4+CD25+ T reg cells protected neonatal LATY136F mice from developing this disease. These T reg cells effectively controlled expansion of CD4+ T cells in LATY136F mice likely via granzymes and/or TGF-β–mediated suppression. Furthermore, ectopic expression of Foxp3 conferred a suppressive function in LATY136F T cells. Our data indicate that the LAT–PLC-γ1 interaction plays a critical role in Foxp3 expression and the development of CD4+CD25+ T reg cells

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 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 Normal peripheral T-cell function in c-Fos-deficient mice.

1994 ◽  
Vol 14 (3) ◽  
pp. 1566-1574 ◽  
Author(s):  
J Jain ◽  
E A Nalefski ◽  
P G McCaffrey ◽  
R S Johnson ◽  
B M Spiegelman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Family Members ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Activated T Cells ◽  
Peripheral T Cells ◽  
Deficient Mice

The ubiquitous transcription factors Fos and Jun are rapidly induced in T cells stimulated through the T-cell antigen receptor and regulate transcription of cytokines, including interleukin 2, in activated T cells. Since positive and negative selection of thymocytes during T-cell development also depends on activation through the T-cell receptor, Fos and Jun may play a role in thymocyte development as well. Fos and Jun act at several regulatory elements in the interleukin 2 promoter, including the AP-1 and NFAT sites. Using antisera specific to individual Fos and Jun family members, we show that c-Fos as well as other Fos family members are present in the inducible AP-1 and NFAT complexes of activated murine T cells. Nevertheless, c-Fos is not absolutely required for the development or function of peripheral T cells, as shown by using mice in which both copies of the c-fos gene were disrupted by targeted mutagenesis. c-Fos-deficient mice were comparable to wild-type mice in their patterns of thymocyte development and in the ability of their peripheral T cells to proliferate and produce several cytokines in response to T-cell receptor stimulation. Our results suggest that other Fos family members may be capable of substituting functionally for c-Fos during T-cell development and cytokine gene transcription in activated T cells.

scholarly journals The Effects of TLR Activation on T-Cell Development and Differentiation

2012 ◽  
Vol 2012 ◽  
pp. 1-32 ◽  
Author(s):  
Bo Jin ◽  
Tao Sun ◽  
Xiao-Hong Yu ◽  
Ying-Xiang Yang ◽  
Anthony E. T. Yeo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Development ◽  
Cell Receptor ◽  
Treg Cells ◽  
Cell Development ◽  
T Cell Subsets ◽  
Follicular Helper ◽  
Development And Differentiation

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed.

scholarly journals Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells

2001 ◽  
Vol 194 (1) ◽  
pp. 99-106 ◽  
Author(s):  
David Allman ◽  
Fredrick G. Karnell ◽  
Jennifer A. Punt ◽  
Sonia Bakkour ◽  
Lanwei Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Surface Proteins ◽  
Lineage Commitment ◽  
Double Positive ◽  
Hematopoietic Stem ◽  
Multipotent Progenitor Cells

Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4+CD8+ double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2−/−) or Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)−/− mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2−/− progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3ε and pre-Tα mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2−/− mice with a TCRβ transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell–specific signals associated with development of DP thymocytes.

scholarly journals Development of all CD4 T lineages requires nuclear factor TOX

2008 ◽  
Vol 205 (1) ◽  
pp. 245-256 ◽  
Author(s):  
Parinaz Aliahmad ◽  
Jonathan Kaye
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Developmental Pathway ◽  
Histocompatibility Complex ◽  
T Cell Receptor Signaling ◽  
Killer T Cells ◽  
Deficient Mice ◽  
Cell Receptor Signaling

CD8+ cytotoxic and CD4+ helper/inducer T cells develop from common thymocyte precursors that express both CD4 and CD8 molecules. Upon T cell receptor signaling, these cells initiate a differentiation program that includes complex changes in CD4 and CD8 expression, allowing identification of transitional intermediates in this developmental pathway. Little is known about regulation of these early transitions or their specific importance to CD4 and CD8 T cell development. Here, we show a severe block at the CD4loCD8lo transitional stage of positive selection caused by loss of the nuclear HMG box protein TOX. As a result, CD4 lineage T cells, including regulatory T and CD1d-dependent natural killer T cells, fail to develop. In contrast, functional CD8+ T cells develop in TOX-deficient mice. Our data suggest that TOX-dependent transition to the CD4+CD8lo stage is required for continued development of class II major histocompatibility complex–specific T cells, regardless of ultimate lineage fate.

scholarly journals Phospholipase Cγ1 is essential for T cell development, activation, and tolerance

2010 ◽  
Vol 207 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Guoping Fu ◽  
Yuhong Chen ◽  
Mei Yu ◽  
Andy Podd ◽  
James Schuman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Phospholipase Cγ1 ◽  
T Cell Biology ◽  
Single Positive ◽  
And Function

Phospholipase Cγ1 (PLCγ1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCγ1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLCγ1. We demonstrate that PLCγ1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-κB. Importantly, PLCγ1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCγ1 is essential for T cell development, activation, and tolerance.

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