scholarly journals Zeb1 represses TCR signaling, promotes the proliferation of T cell progenitors and is essential for NK1.1+ T cell development

2020 ◽  
Author(s):  
Jiang Zhang ◽  
Mélanie Wencker ◽  
Quentin Marliac ◽  
Aurore Berton ◽  
Uzma Hasan ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Tcr Signaling ◽  
T Cell Progenitors

scholarly journals RasGRP1 Transmits Prodifferentiation TCR Signaling That Is Crucial for CD4 T Cell Development

2006 ◽  
Vol 177 (3) ◽  
pp. 1470-1480 ◽  
Author(s):  
John J. Priatel ◽  
Xiaoxi Chen ◽  
Salim Dhanji ◽  
Ninan Abraham ◽  
Hung-Sia Teh
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cd4 T Cell ◽  
Tcr Signaling

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 Disruption of αβ but not of γδ T cell development by overexpression of the helix–loop–helix protein Id3 in committed T cell progenitors

1999 ◽  
Vol 18 (10) ◽  
pp. 2793-2802 ◽  
Author(s):  
Bianca Blom ◽  
Mirjam H.M. Heemskerk ◽  
Martie C.M. Verschuren ◽  
Jacques J.M. van Dongen ◽  
Alexander P.A. Stegmann ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Γδ T Cell ◽  
Helix Loop Helix ◽  
T Cell Progenitors

scholarly journals Regulation of positive and negative selection and TCR signaling during thymic T cell development by capicua

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Soeun Kim ◽  
Guk-Yeol Park ◽  
Jong Seok Park ◽  
Jiho Park ◽  
Hyebeen Hong ◽  
...  
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
Target Genes ◽  
Selection Process ◽  
T Cell Development ◽  
Cell Development ◽  
Calcium Flux ◽  
Thymic Selection ◽  
Tcr Signaling ◽  
Selection Of

Central tolerance is achieved through positive and negative selection of thymocytes mediated by T cell receptor (TCR) signaling strength. Thus, dysregulation of the thymic selection process often leads to autoimmunity. Here, we show that Capicua (CIC), a transcriptional repressor that suppresses autoimmunity, controls the thymic selection process. Loss of CIC prior to T-cell lineage commitment impairs both positive and negative selection of thymocytes. CIC deficiency attenuated TCR signaling in CD4+CD8+ double-positive (DP) cells, as evidenced by a decrease in CD5 and phospho-ERK levels and calcium flux. We identified Spry4, Dusp4, Dusp6, and Spred1 as CIC target genes that could inhibit TCR signaling in DP cells. Furthermore, impaired positive selection and TCR signaling were partially rescued in Cic and Spry4 double mutant mice. Our findings indicate that CIC is a transcription factor required for thymic T cell development and suggests that CIC acts at multiple stages of T cell development and differentiation to prevent autoimmunity.

mTORC1 Inactivation Prevents and Eradicates Acute Lymphoblastic T-Cell Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1211-1211
Author(s):  
Takayuki Hoshii ◽  
Atsuo Kasada ◽  
Tomoki Hatakeyama ◽  
Masashi Ohtani ◽  
Yuko Tadokoro ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cyclin D3 ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Rapamycin Treatment ◽  
T Cell Progenitors

Abstract mTOR is a serine/threonine kinase that has a central role in the regulation of cell growth and cell metabolism and forms two functionally different complexes, named mTORC1 and mTORC2. Despite the effectiveness of rapamycin, an allosteric mTOR inhibitor, in immunosuppression, the precise roles of mTORCs in T-cell development remain unclear. Here we show that mTORC1 plays a critical role in the earliest development of T-cell progenitors. To understand the physiological role of mTORC1 in T-cell development, we evaluated the effects of mTORC1 inhibition by rapamycin treatment or the genetic deletion of the Raptor gene, an essential component of mTORC1. Raptor deficiency dramatically inhibited the development of CD4/CD8 double-positive (DP) cells. Rapamycin treatment produced similar defects, but to a lesser extent. Deficiency of Raptor, but not Rictor, a mTORC2 component, resulted in abnormality of cell cycle of early T-cell progenitors, associated with instability of the Cyclin D3/CDK6 complex, indicating that mTORC1 and 2 control T-cell development in different manners. When we treated T-cells with a proteasome inhibitor, MG-132, in vitro, the reduction of Cyclin D3 and CDK6 by mTORC1 inactivation was reversed. These data suggest that mTORC1 activity may control the Cyclin D3/CDK6 complex via post-transcriptional mechanisms. In a model of myeloproliferative neoplasm (MPN) and T-cell leukemia (T-ALL) evoked by Kras activation, rapamycin treatment prevents development of T-ALL, but not MPN. After the onset of T-ALL, rapamycin-insensitive Notch-driven T-ALL cells survived in vivo. Raptor deficiency dramatically inhibited proliferation of oncogenic Kras–expressing T-cell progenitors and prevents the development of T-ALL, but not MPN. In contrast to T-cell progenitors, cell cycle of myeloid progenitors was not affected by mTORC1 inactivation. Phosphorylation of p70S6K and 4E-BP1, direct substrates of mTORC1, was apparently decreased in Raptor-deficient myeloid cells. Interestingly, consistent with hypo-phosphorylation of p70S6K and 4E-BP1, rates of newly synthesized protein were significantly reduced in cycling Raptor-deficient progenitors. These data indicate that the impact of mTORC1 deficiency on cell cycle status varies substantially depending on the cell context. In addition, we evaluated the effect of hyperactivation of mTORC1 by Tsc1 deletion on the behavior of T-ALL. Tsc1 deficiency shortened survival, and promoted the cell proliferation, as well as the dissemination of active Notch-driven T-ALL cells in non-hematopoietic tissues. However, strikingly, Raptor deficiency resulted in efficient leukemia eradication. Thus, understanding the cell-context-dependent role of mTORC1 illustrates the potential importance of mTOR signals as therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness

2017 ◽  
Vol 214 (3) ◽  
pp. 833-849 ◽  
Author(s):  
Lih-Yun Hsu ◽  
Debra A. Cheng ◽  
Yiling Chen ◽  
Hong-Erh Liang ◽  
Arthur Weiss
Keyword(s):  
T Cell ◽  
Negative Selection ◽  
T Cell Development ◽  
Cell Development ◽  
Receptor Expression ◽  
Peripheral Tolerance ◽  
Mutant Mice ◽  
Inhibitory Receptor ◽  
Inhibitory Receptors ◽  
Tcr Signaling

Zap70 plays a critical role in normal T cell development and T cell function. However, little is known about how perturbation of allosteric autoinhibitory mechanisms in Zap70 impacts T cell biology. Here, we analyze mice with a hypermorphic Zap70 mutation, W131A, which destabilizes the autoinhibitory conformation of Zap70, rendering the kinase in a semiactive state. W131A mutant mice with wild-type T cell receptor (TCR) repertoires exhibited relatively normal T cell development. However, crossing the W131A mutant mice to OTII TCR transgenic mice resulted in increased negative selection of OTII+ thymocytes and in increased thymic and peripheral T regulatory cells. Strikingly, increased basal TCR signaling was associated with a marked increase in inhibitory receptor expression and with T cells that were relatively refractory to TCR stimulation. PD-1 inhibitory receptor blockade partially reversed T cell unresponsiveness. Collectively, disruption of normal Zap70 autoinhibition engaged negative feedback mechanisms by which negative selection and inhibitory receptors restrain TCR signaling to enforce both central and peripheral tolerance.

scholarly journals PP6 Controls T Cell Development and Homeostasis by Negatively Regulating Distal TCR Signaling

2015 ◽  
Vol 194 (4) ◽  
pp. 1654-1664 ◽  
Author(s):  
Jian Ye ◽  
Hao Shi ◽  
Ye Shen ◽  
Chao Peng ◽  
Yan Liu ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Tcr Signaling

scholarly journals T Cell Receptor β Chain Lacking the Large Solvent-exposed Cβ FG Loop Supports Normal α/β T Cell Development and Function in Transgenic Mice

1999 ◽  
Vol 189 (10) ◽  
pp. 1679-1684 ◽  
Author(s):  
Sylvie Degermann ◽  
Giuseppina Sollami ◽  
Klaus Karjalainen
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Tcr Signaling ◽  
Unique Structural Feature ◽  
Immunoglobulin Domain ◽  
And Function ◽  
Β Chain

The striking and unique structural feature of the T cell receptor (TCR) β chain is the bulky solvent-exposed FG loop on the Cβ domain, the size of almost half an immunoglobulin domain. The location and size of this loop suggested immediately that it could be a crucial structural link between the invariant CD3 subunits and antigen-recognizing α/β chains during TCR signaling. However, functional analysis does not support the above notion, since transgene coding for TCR β chain lacking the complete FG loop supports normal α/β T cell development and function.

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