Presenilins regulate αβ T cell development by modulating TCR signaling

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.

Download Full-text

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

eLife ◽

10.7554/elife.71769 ◽

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.

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.20161575 ◽

2017 ◽

Vol 214 (3) ◽

pp. 833-849 ◽

Cited By ~ 5

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.

Download Full-text

Pontin is required for pre-TCR signaling at the β-selection checkpoint in T cell development

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2014.03.092 ◽

2014 ◽

Vol 447 (1) ◽

pp. 44-50 ◽

Cited By ~ 2

Author(s):

Kyungjin Boo ◽

Sung Hee Baek ◽

Ho Lee

Keyword(s):

T Cell ◽

T Cell Development ◽

Cell Development ◽

Tcr Signaling

Download Full-text

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

The Journal of Immunology ◽

10.4049/jimmunol.1401692 ◽

2015 ◽

Vol 194 (4) ◽

pp. 1654-1664 ◽

Cited By ~ 5

Author(s):

Jian Ye ◽

Hao Shi ◽

Ye Shen ◽

Chao Peng ◽

Yan Liu ◽

...

Keyword(s):

T Cell ◽

T Cell Development ◽

Cell Development ◽

Tcr Signaling

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.189.10.1679 ◽

1999 ◽

Vol 189 (10) ◽

pp. 1679-1684 ◽

Cited By ~ 11

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.

Download Full-text

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

10.1101/2021.07.11.451936 ◽

2021 ◽

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, the 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 impaired 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 suggest that CIC acts at multiple stages of T cell development and differentiation to prevent autoimmunity.

Download Full-text

Indian hedgehog (Ihh) both promotes and restricts thymocyte differentiation

Blood ◽

10.1182/blood-2008-03-144840 ◽

2009 ◽

Vol 113 (10) ◽

pp. 2217-2228 ◽

Cited By ~ 27

Author(s):

Susan V. Outram ◽

Ariadne L. Hager-Theodorides ◽

Divya K. Shah ◽

Nicola J. Rowbotham ◽

Ekati Drakopoulou ◽

...

Keyword(s):

T Cell ◽

T Cell Development ◽

Cell Development ◽

Conditional Knockout ◽

Indian Hedgehog ◽

Double Negative ◽

Wild Type ◽

Thymocyte Development ◽

Tcr Signaling ◽

Double Positive

Abstract We show that Indian Hedgehog (Ihh) regulates T-cell development and homeostasis in both fetal and adult thymus, controlling thymocyte number. Fetal Ihh−/− thymi had reduced differentiation to double-positive (DP) cell and reduced cell numbers compared with wild-type littermates. Surprisingly, fetal Ihh+/− thymi had increased thymocyte numbers and proportion of DP cells relative to wild type, indicating that Ihh also negatively regulates thymocyte development. In vitro treatment of thymus explants with exogenous recombinant Hedgehog protein promoted thymocyte development in Ihh−/− thymi but inhibited thymocyte development in Ihh+/−, confirming both positive and negative regulatory functions of Ihh. Analysis of Rag−/−Ihh+/− thymi showed that Ihh promotes T-cell development before pre–T-cell receptor (pre-TCR) signaling, but negatively regulates T-cell development only after pre-TCR signaling has taken place. We show that Ihh is most highly expressed by the DP population and that Ihh produced by DP cells feeds back to negatively regulate the differentiation and proliferation of their double-negative progenitors. Thus, differentiation from double-negative to DP cell, and hence the size of the DP population, is dependent on the concentration of Ihh in the thymus. Analysis of Ihh conditional knockout and heterozygote adult mice showed that Ihh also influences thymocyte number in the adult.

Download Full-text