Gimap4 accelerates T-cell death

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 591-599 ◽  
Author(s):  
Silke Schnell ◽  
Corinne Démollière ◽  
Paul van den Berk ◽  
Heinz Jacobs
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Critical Role ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Physiology ◽  
Double Positive ◽  
Pkc Activation ◽  
Null Mutant Mouse

Gimap4, a member of the newly identified GTPase of the immunity-associated protein family (Gimap), is strongly induced by the pre–T-cell receptor in precursor T lymphocytes, transiently shut off in double-positive thymocytes, and reappears after TCR-mediated positive selection. Here, we show that Gimap4 remains expressed constitutively in the cytosol of mature T cells. A C-terminal IQ domain binds calmodulin in the absence of calcium, and conserved PKC phosphorylation motifs are targets of concanavalin A (ConA)– or PMA/ionomycin-induced PKC activation. To address the role of Gimap4 in T-cell physiology, we completed the genomic organization of the gimap4 locus and generated a Gimap4-null mutant mouse. Studies in these mice revealed no critical role of Gimap4 in T-cell development but in the regulation of apoptosis. We have found that Gimap4 accelerates the execution of programmed cell death induced by intrinsic stimuli downstream of caspase-3 activation and phosphatidylserine exposure. Apoptosis directly correlates with the phosphorylation status of Gimap4.

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.

scholarly journals Defined αβ T Cell Receptors with Distinct Ligand Specificities Do Not Require Those Ligands to Signal Double Negative Thymocyte Differentiation

2004 ◽  
Vol 199 (12) ◽  
pp. 1719-1724 ◽  
Author(s):  
Batu Erman ◽  
Terry I. Guinter ◽  
Alfred Singer
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Double Negative ◽  
Antigen Receptors ◽  
Double Positive ◽  
Recombination Activating Gene ◽  
Thymocyte Differentiation ◽  
Deficient Mice

During T cell development in the thymus, pre–T cell receptor (TCR) complexes signal CD4− CD8− (double negative [DN]) thymocytes to differentiate into CD4+ CD8+ (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as αβ TCR or αγ TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although αγ TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if αβ TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined αβ TCR transgenes in recombination activating gene 2−/− pre-Tα−/− double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the αβ TCR transgenes. In this way, this study definitively demonstrates that αβ TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic αβ TCRs signal the DN to DP transition even in the absence of their specific MHC–peptide ligands.

scholarly journals Survivin Loss in Thymocytes Triggers p53-mediated Growth Arrest and p53-independent Cell Death

2004 ◽  
Vol 199 (3) ◽  
pp. 399-410 ◽  
Author(s):  
Hitoshi Okada ◽  
Chris Bakal ◽  
Arda Shahinian ◽  
Andrew Elia ◽  
Andrew Wakeham ◽  
...  
Keyword(s):  
Cell Death ◽  
Critical Role ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Double Positive ◽  
Developmental Defects ◽  
Cycle Arrest ◽  
Tightly Coupled ◽  
Early Embryonic Stage ◽  
P53 Inactivation

Because survivin-null embryos die at an early embryonic stage, the role of survivin in thymocyte development is unknown. We have investigated the role by deleting the survivin gene only in the T lineage and show here that loss of survivin blocks the transition from CD4− CD8− double negative (DN) thymocytes to CD4+ CD8+ double positive cells. Although the pre–T cell receptor signaling pathway is intact in survivin-deficient thymocytes, the cells cannot respond to its signals. In response to proliferative stimuli, cycling survivin-deficient DN cells exhibit cell cycle arrest, a spindle formation defect, and increased cell death. Strikingly, loss of survivin activates the tumor suppressor p53. However, the developmental defects caused by survivin deficiency cannot be rescued by p53 inactivation or introduction of Bcl-2. These lines of evidence indicate that developing thymocytes depend on the cytoprotective function of survivin and that this function is tightly coupled to cell proliferation but independent of p53 and Bcl-2. Thus, survivin plays a critical role in early thymocyte development.

scholarly journals VßGene Family Usage in Spontaneous Lymphomas of AKR Mice: Evidence for Defective Clonal Deletion

1992 ◽  
Vol 2 (2) ◽  
pp. 95-101 ◽  
Author(s):  
Cees de Heer ◽  
Bernard de Geus ◽  
Henk-Jan Schuurma ◽  
Henk Van Loveren ◽  
Jan Rozing
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Mesenteric Lymph Nodes ◽  
Double Positive ◽  
Clonal Deletion ◽  
Lymphoma Cells ◽  
Single Positive ◽  
Akr Mice

T-cell receptor (TCR)ß-chain usage and expression of the CD3, CD4, and CD8 differentiation antigens were analyzed in 14 spontaneous AKR lymphomas. Lymphoma cells massively infiltrated and/or proliferated in the organs analyzed (thymus, spleen, and mesenteric lymph nodes), giving rise to a loss of organ structure. One lymphoma occurred only in the thymus, and failed to express CD3, CD4, and CD8. All other lymphomas expressed the CD3/TCR complex. With respect to CD4 and CD8 expression, the lymphomas were either double-negative (DN), double-positive (DP), or single-positive (SP). The frequency of DP (CD4+8+) lymphomas was low compared to the frequency of DP thymocytes in a normal AKR thymus. A substantial heterogeneity was seen in the intensity of CD4 and CD8 expression among various lymphomas, which was independent of the level of CD3 expression. Considering TCR Vßgene family usage, 2 out of 14 lymphomas expressed Vß6. Normally, Vß6+thymocytes are deleted from the thymocyte pool at the immature DP stage of T-cell development in AKR mice. These data support the hypothesis that the lymphocytes in the immature DP stage of T-cell development are susceptible to the induction of AKR lymphomagenesis. The presence of Vß6+lymphoma cells indicates that the lymphomagenesis is accompanied by a defective clonal deletion of cells expressing a possible autoreactive TCR.

scholarly journals Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas

2015 ◽  
Vol 112 (25) ◽  
pp. 7773-7778 ◽  
Author(s):  
Hyung-Ok Lee ◽  
Xiao He ◽  
Jayati Mookerjee-Basu ◽  
Dai Zhongping ◽  
Xiang Hua ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Human T Cell

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell–specific ThPOK transgene (ThPOKconst mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOKconst RAG-deficient mice, which promotes development to the CD4+8+ (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

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.

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

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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