scholarly journals A Stat5b transgene is capable of inducing CD8+ lymphoblastic lymphoma in the absence of normal TCR/MHC signaling

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 344-350 ◽  
Author(s):  
Katherine Bessette ◽  
Mark L. Lang ◽  
Roy A. Fava ◽  
Martin Grundy ◽  
Jennifer Heinen ◽  
...  
Keyword(s):  
T Cell ◽  
Significant Proportion ◽  
Cell Receptor ◽  
Tumor Formation ◽  
Tcr Signaling ◽  
Double Positive ◽  
Oncogenic Potential ◽  
Histocompatibility Complex ◽  
T Cell Lymphomas ◽  
Tcr Signals

Stat5 proteins are critical signaling molecules activated by many cytokines. Within the immune system, Stat5 plays important roles related to the development of thymocytes and proliferation of T cells. Stat5 has been implicated in malignant transformation, and moreover, the activated tyrosine phosphorylated form of Stat5 is frequently observed in human lymphomas. We previously demonstrated the oncogenic potential of Stat5, with thymic lymphoblastic lymphomas developing in a significant proportion of transgenic (TG) mice overexpressing Stat5a or Stat5b in lymphocytes. In addition, immunization or expression of a T-cell receptor (TCR) transgene augmented the rate of tumor formation. Here, we investigate the mechanism of Stat5-mediated lymphomagenesis by exploring the contributions of major histocompatibility complex (MHC)/TCR and pre-TCR signals. We present data demonstrating that Stat5b TG mice unexpectedly develop CD8+ lymphoma even in the absence of either pre-TCR signaling or normal thymic selection. Indeed, acceleration of Stat5b transgene-mediated lymphoma occurred on TCRα−/− and pre-TCRα−/− backgrounds. In light of these data, we propose a model in which alterations in T-cell development at the double-negative/double-positive (DN/DP) stages cooperate with cytokine-mediated pathways in immature thymocytes to give rise to lymphoblastic T-cell lymphomas in Stat5b TG mice.

scholarly journals The Loss of PTEN Allows TCR αβ Lineage Thymocytes to Bypass IL-7 and Pre-TCR–mediated Signaling

2004 ◽  
Vol 200 (7) ◽  
pp. 883-894 ◽  
Author(s):  
Thijs J. Hagenbeek ◽  
Marianne Naspetti ◽  
Fabrice Malergue ◽  
Fabien Garçon ◽  
Jacques A. Nunès ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Double Positive ◽  
Important Regulator ◽  
Tcr Signals ◽  
Phosphatase And Tensin Homologue ◽  
Deficient Mice

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates cell survival and proliferation mediated by phosphoinositol 3 kinases. We have explored the role of the phosphoinositol(3,4,5)P3-phosphatase PTEN in T cell development by analyzing mice with a T cell–specific deletion of PTEN. Ptenflox/floxLck-Cre mice developed thymic lymphomas, but before the onset of tumors, they showed normal thymic cellularity. To reveal a regulatory role of PTEN in proliferation of developing T cells we have crossed PTEN-deficient mice with mice deficient for interleukin (IL)-7 receptor and pre–T cell receptor (TCR) signaling. Analysis of mice deficient for Pten and CD3γ; Pten and γc; or Pten, γc, and Rag2 revealed that deletion of PTEN can substitute for both IL-7 and pre-TCR signals. These double- and triple-deficient mice all develop normal levels of CD4CD8 double negative and double positive thymocytes. These data indicate that PTEN is an important regulator of proliferation of developing T cells in the thymus.

scholarly journals Loss of tonic T-cell receptor signals alters the generation but not the persistence of CD8+ memory T cells

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5560-5570 ◽  
Author(s):  
Karla R. Wiehagen ◽  
Evann Corbo ◽  
Michelle Schmidt ◽  
Haina Shin ◽  
E. John Wherry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Sh2 Domain ◽  
Normal Numbers ◽  
Tcr Signaling ◽  
Tcr Signals

Abstract The requirements for tonic T-cell receptor (TCR) signaling in CD8+ memory T-cell generation and homeostasis are poorly defined. The SRC homology 2 (SH2)-domain–containing leukocyte protein of 76 kDa (SLP-76) is critical for proximal TCR-generated signaling. We used temporally mediated deletion of SLP-76 to interrupt tonic and activating TCR signals after clearance of the lymphocytic choriomeningitis virus (LCMV). SLP-76–dependent signals are required during the contraction phase of the immune response for the normal generation of CD8 memory precursor cells. Conversely, LCMV-specific memory CD8 T cells generated in the presence of SLP-76 and then acutely deprived of TCR-mediated signals persist in vivo in normal numbers for more than 40 weeks. Tonic TCR signals are not required for the transition of the memory pool toward a central memory phenotype, but the absence of SLP-76 during memory homeostasis substantially alters the kinetics. Our data are consistent with a model in which tonic TCR signals are required at multiple stages of differentiation, but are dispensable for memory CD8 T-cell persistence.

scholarly journals Pre–T Cell Receptor (Tcr) and Tcr-Controlled Checkpoints in T Cell Differentiation Are Set by Ikaros

1999 ◽  
Vol 190 (8) ◽  
pp. 1039-1048 ◽  
Author(s):  
Susan Winandy ◽  
Li Wu ◽  
Jin-Hong Wang ◽  
Katia Georgopoulos
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Differentiation ◽  
Tcr Signaling ◽  
Double Positive ◽  
Single Positive ◽  
T Cell Malignancies ◽  
Deficient Mice

T cell differentiation relies on pre–T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway. Here, we show that two of these T cell differentiation checkpoints are regulated by Ikaros. In the absence of Ikaros, double negative thymocytes can differentiate to the double positive stage without expression of a pre-TCR complex. Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros. Nonetheless, in Ikaros-deficient thymocytes, the requirement of pre-TCR expression for expansion of immature thymocytes as they progress to the double positive stage is still maintained, and the T cell malignancies that invariably arise in the thymus of Ikaros-deficient mice are dependent on either pre-TCR or TCR signaling. We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

scholarly journals The transcription factor Gli3 regulates differentiation of fetal CD4–CD8– double-negative thymocytes

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1296-1304 ◽  
Author(s):  
Ariadne L. Hager-Theodorides ◽  
Johannes T. Dessens ◽  
Susan V. Outram ◽  
Tessa Crompton
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Differentiation ◽  
Double Negative ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Dose Dependent

AbstractGlioblastoma 3 (Gli3) is a transcription factor involved in patterning and oncogenesis. Here, we demonstrate a role for Gli3 in thymocyte development. Gli3 is differentially expressed in fetal CD4–CD8– double-negative (DN) thymocytes and is most highly expressed at the CD44+ CD25– DN (DN1) and CD44–CD25– (DN4) stages of development but was not detected in adult thymocytes. Analysis of null mutants showed that Gli3 is involved at the transitions from DN1 to CD44+ CD25+ DN (DN2) cell and from DN to CD4+CD8+ double-positive (DP) cell. Gli3 is required for differentiation from DN to DP thymocyte, after pre–T-cell receptor (TCR) signaling but is not necessary for pre-TCR–induced proliferation or survival. The effect of Gli3 was dose dependent, suggesting its direct involvement in the transcriptional regulation of genes controlling T-cell differentiation during fetal development.

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 Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways

2002 ◽  
Vol 195 (9) ◽  
pp. 1103-1114 ◽  
Author(s):  
Lucinda F. Reynolds ◽  
Lesley A. Smyth ◽  
Trisha Norton ◽  
Norman Freshney ◽  
Julian Downward ◽  
...  
Keyword(s):  
T Cell ◽  
Phospholipase C ◽  
T Cell Receptor ◽  
Genetic System ◽  
Cell Receptor ◽  
Calcium Flux ◽  
Double Positive ◽  
Signaling Complex ◽  
Tcr Signals ◽  
Phosphoinositide 3 Kinase

Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4+CD8+ double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-γ1 (PLCγ1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCγ1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCγ1 and the adaptor molecule Src homology 2 domain–containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.

scholarly journals Restricting Zap70 Expression to CD4+CD8+ Thymocytes Reveals a T Cell Receptor–dependent Proofreading Mechanism Controlling the Completion of Positive Selection

2003 ◽  
Vol 197 (3) ◽  
pp. 363-373 ◽  
Author(s):  
Xiaolong Liu ◽  
Anthony Adams ◽  
Kathryn F. Wildt ◽  
Bruce Aronow ◽  
Lionel Feigenbaum ◽  
...  
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Novel Approach ◽  
Single Positive ◽  
Tcr Signals

Although T cell receptor (TCR) signals are essential for intrathymic T cell–positive selection, it remains controversial whether they only serve to initiate this process, or whether they are required throughout to promote thymocyte differentiation and survival. To address this issue, we have devised a novel approach to interfere with thymocyte TCR signaling in a developmental stage-specific manner in vivo. We have reconstituted mice deficient for Zap70, a tyrosine kinase required for TCR signaling and normally expressed throughout T cell development, with a Zap70 transgene driven by the adenosine deaminase (ADA) gene enhancer, which is active in CD4+CD8+ thymocytes but inactive in CD4+ or CD8+ single-positive (SP) thymocytes. In such mice, termination of Zap70 expression impaired TCR signal transduction and arrested thymocyte development after the initiation, but before the completion, of positive selection. Arrested thymocytes had terminated Rag gene expression and up-regulated TCR and Bcl-2 expression, but failed to differentiate into mature CD4 or CD8 SP thymocytes, to be rescued from death by neglect or to sustain interleukin 7Rα expression. These observations identify a TCR-dependent proofreading mechanism that verifies thymocyte TCR specificity and differentiation choices before the completion of positive selection.

scholarly journals Thymic progenitors of TCRαβ+ CD8αα intestinal intraepithelial lymphocytes require RasGRP1 for development

2017 ◽  
Vol 214 (8) ◽  
pp. 2421-2435 ◽  
Author(s):  
Dominic P. Golec ◽  
Romy E. Hoeppli ◽  
Laura M. Henao Caviedes ◽  
Jillian McCann ◽  
Megan K. Levings ◽  
...  
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Clonal Deletion ◽  
Selection Processes ◽  
Tcr Signals

Strong T cell receptor (TCR) signaling largely induces cell death during thymocyte development, whereas weak TCR signals induce positive selection. However, some T cell lineages require strong TCR signals for differentiation through a process termed agonist selection. The signaling relationships that underlie these three fates are unknown. RasGRP1 is a Ras activator required to transmit weak TCR signals leading to positive selection. Here, we report that, despite being dispensable for thymocyte clonal deletion, RasGRP1 is critical for agonist selection of TCRαβ+CD8αα intraepithelial lymphocyte (IEL) progenitors (IELps), even though both outcomes require strong TCR signaling. Bim deficiency rescued IELp development in RasGRP1−/− mice, suggesting that RasGRP1 functions to promote survival during IELp generation. Additionally, expression of CD122 and the adhesion molecules α4β7 and CD103 define distinct IELp subsets with differing abilities to generate TCRαβ+CD8αα IEL in vivo. These findings demonstrate that RasGRP1-dependent signaling underpins thymic selection processes induced by both weak and strong TCR signals and is differentially required for fate decisions derived from a strong TCR stimulus.

scholarly journals Stat5 Synergizes with T Cell Receptor/Antigen Stimulation in the Development of Lymphoblastic Lymphoma

2003 ◽  
Vol 198 (1) ◽  
pp. 79-89 ◽  
Author(s):  
John A. Kelly ◽  
Rosanne Spolski ◽  
Panu E. Kovanen ◽  
Takeshi Suzuki ◽  
Julie Bollenbacher ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Lymphoblastic Lymphoma ◽  
Signal Transducer ◽  
Oncogenic Potential ◽  
Stat Proteins ◽  
T Cell Lymphomas ◽  
Wide Range

Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II–restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

scholarly journals CD8 Coreceptor Extinction in Signaled CD4+CD8+ Thymocytes: Coordinate Roles for Both Transcriptional and Posttranscriptional Regulatory Mechanisms in Developing Thymocytes

2000 ◽  
Vol 20 (11) ◽  
pp. 3852-3859 ◽  
Author(s):  
Ricardo Cibotti ◽  
Avinash Bhandoola ◽  
Terry I. Guinter ◽  
Susan O. Sharrow ◽  
Alfred Singer
Keyword(s):  
T Cell ◽  
Gene Transcription ◽  
Expression Patterns ◽  
Rna Stability ◽  
Cell Receptor ◽  
Regulatory Mechanisms ◽  
Double Positive ◽  
Transcriptional Regulatory ◽  
Transcriptional Regulatory Mechanisms ◽  
Tcr Signals

ABSTRACT T-cell development in the thymus is characterized by changing expression patterns of CD4 and CD8 coreceptor molecules and by changes in CD4 and CD8 gene transcription. In response to T-cell receptor (TCR) signals, thymocytes progress through developmental transitions, such as conversion of CD4+CD8+ (double-positive [DP]) thymocytes into intermediate CD4+CD8−thymocytes, that appear to require more-rapid changes in coreceptor expression than can be accomplished by transcriptional regulation alone. Consequently, we considered the possibility that TCR stimulation of DP thymocytes not only affects coreceptor gene transcription but also affects coreceptor RNA stability. Indeed, we found that TCR signals in DP thymocytes rapidly destabilized preexisting CD4 and CD8 coreceptor RNAs, resulting in their rapid elimination. Destabilization of coreceptor RNA was shown for CD8α to be dependent on target sequences in the noncoding region of the RNA. TCR signals also differentially affected coreceptor gene transcription in DP thymocytes, terminating CD8α gene transcription but only transiently reducing CD4 gene transcription. Thus, posttranscriptional and transcriptional regulatory mechanisms act coordinately in signaled DP thymocytes to promote the rapid conversion of these cells into intermediate CD4+CD8− thymocytes. We suggest that destabilization of preexisting coreceptor RNAs is a mechanism by which coreceptor expression in developing thymocytes is rapidly altered at critical points in the differentiation of these cells.

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