scholarly journals Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by compacting super-enhancers

2021 ◽  
Author(s):  
Delong Feng ◽  
Yanhong Chen ◽  
Ranran Dai ◽  
Shasha Bian ◽  
Wei Xue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Regulation Mechanism ◽  
Thymocyte Development ◽  
Double Positive ◽  
Enhancer Activity ◽  
Cell Identity ◽  
Single Positive

Abstract CD4+ and CD8+ double-positive (DP) thymocytes are at a crucial stage during the T cell development in the thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCRβ. Then DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, Regulatory T cells, or invariant nature kill T cells (iNKT) according to the TCR signal. Chromatin organizer SATB1 is highly expressed in DP cells and plays an essential role in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing assay of SATB1-deficient thymocytes showed that the cell identity of DP thymocytes was changed, and the genes specifically highly expressed in DP cells were down-regulated. The super-enhancers regulate the expressions of the DP-specific genes, and the SATB1 deficiency reduced the super-enhancer activity. Hi-C data showed that interactions in super-enhancers and between super-enhancers and promoters decreased in SATB1 deficient thymocytes. We further explored the regulation mechanism of two SATB1-regulating genes, Ets2 and Bcl6, in DP cells and found that the knockout of the super-enhancers of these two genes impaired the development of DP cells. Our research reveals that SATB1 globally regulates super-enhancers of DP cells and promotes the establishment of DP cell identity, which helps understand the role of SATB1 in thymocyte development.

scholarly journals IL-7 Receptor Signals Inhibit Expression of Transcription Factors TCF-1, LEF-1, and RORγt

2004 ◽  
Vol 200 (6) ◽  
pp. 797-803 ◽  
Author(s):  
Qing Yu ◽  
Batu Erman ◽  
Jung-Hyun Park ◽  
Lionel Feigenbaum ◽  
Alfred Singer
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Target Genes ◽  
Cell Receptor ◽  
Inhibitory Influence ◽  
Thymocyte Development ◽  
Double Positive ◽  
Downstream Target ◽  
Single Positive

Intrathymic T cell development depends on signals transduced by both T cell receptor and cytokine receptors. Early CD4−CD8− (double negative) thymocytes require interleukin (IL)-7 receptor (IL-7R) signals for survival and proliferation, but IL-7R signals are normally extinguished by the immature single positive (ISP) stage of thymocyte development. We now demonstrate that IL-7R signals inhibit expression of transcription factors TCF-1, LEF-1, and RORγt that are required for the ISP to double positive (DP) transition in the thymus. In addition, we demonstrate that IL-7R signals also inhibit TCF-1 and LEF-1 expression in mature peripheral T cells. Thus, the present work has identified several important downstream target genes of IL-7R signaling in T cells and thymocytes that provide a molecular mechanism for the inhibitory influence of IL-7R signaling on DP thymocyte development. We conclude that IL-7R signals down-regulate transcription factors required for the ISP to DP transition and so must be terminated by the ISP stage of thymocyte development.

scholarly journals Interleukin 4 expressed in situ selectively alters thymocyte development.

1991 ◽  
Vol 173 (1) ◽  
pp. 89-100 ◽  
Author(s):  
D B Lewis ◽  
C C Yu ◽  
K A Forbush ◽  
J Carpenter ◽  
T A Sato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Thymocyte Development ◽  
Double Positive ◽  
Peripheral T Cells ◽  
Single Positive ◽  
And Control

Using a transgenic mouse model we show that increased intrathymic expression of interleukin 4 (IL-4) significantly perturbs the development of thymocytes. Transgenic double-positive (CD4+CD8+) thymocytes, which are present in dramatically reduced numbers, exhibit increased T cell receptor (TCR) expression and increased mobilization of calcium mediated by these receptors. In contrast, transgenic single-positive (CD4+CD8- and CD4-CD8+) thymocytes and peripheral T cells exhibit decreased TCR-mediated calcium mobilization. The development of CD4-CD8+ thymocytes is significantly perturbed by IL-4 expressed in vivo; only peripheral CD4+ T cells are found in significant numbers in transgenic mice, while CD4-CD8+ thymocytes are present in increased numbers, apparently because of their failure to emigrate to the periphery. In contrast to these selective effects on T cell development, no significant differences in the numbers of B cells or mast cells, or in the plasma levels of IgE and IgG1 are observed between transgenic and control mice. These observations suggest that IL-4 in vivo exerts its major effects locally rather than systemically, even when its expression is constitutively increased.

Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury

2018 ◽  
Vol 46 (4) ◽  
pp. 441-449
Author(s):  
Sowmya Angusamy ◽  
Tamer Mansour ◽  
Mohammed Abdulmageed ◽  
Rachel Han ◽  
Brian C. Schutte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
T Cell Development ◽  
Adaptive Immune System ◽  
Cell Development ◽  
Thymocyte Development ◽  
Double Positive ◽  
Neonatal Mice ◽  
Single Positive

Abstract Background: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. Methods: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. Results: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. Conclusions: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

scholarly journals T-cell receptor α enhancer is inactivated in αβ T lymphocytes

2015 ◽  
Vol 112 (14) ◽  
pp. E1744-E1753 ◽  
Author(s):  
Beatriz del Blanco ◽  
Úrsula Angulo ◽  
Michael S. Krangel ◽  
Cristina Hernández-Munain
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Germ Line ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Enhancer Activity ◽  
Major Function

The Tcra enhancer (Eα) is essential for Tcra locus germ-line transcription and primary Vα-to-Jα recombination during thymocyte development. We found that Eα is inhibited late during thymocyte differentiation and in αβ T lymphocytes, indicating that it is not required to drive transcription of rearranged Tcra genes. Eα inactivation resulted in the disruption of functional long-range enhancer-promoter interactions and was associated with loss of Eα-dependent histone modifications at promoter and enhancer regions, and reduced expression and recruitment of E2A to the Eα enhanceosome in T cells. Enhancer activity could not be recovered by T-cell activation, by forced expression of E2A or by the up-regulation of this and other transcription factors in the context of T helper differentiation. Our results argue that the major function of Eα is to coordinate the formation of a chromatin hub that drives Vα and Jα germ-line transcription and primary rearrangements in thymocytes and imply the existence of an Eα-independent mechanism to activate transcription of the rearranged Tcra locus in αβ T cells.

scholarly journals Involvement of the TCR Cβ FG Loop in Thymic Selection and T Cell Function

2002 ◽  
Vol 195 (11) ◽  
pp. 1419-1431 ◽  
Author(s):  
Tetsuro Sasada ◽  
Maki Touma ◽  
Hsiu-Ching Chang ◽  
Linda K. Clayton ◽  
Jia-huai Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Negative Selection ◽  
Cell Function ◽  
Side Wall ◽  
Fold Increase ◽  
Cell Receptor ◽  
Double Positive ◽  
Single Positive ◽  
Induced Apoptosis

The asymmetric disposition of T cell receptor (TCR) Cβ and Cα ectodomains creates a cavity with a side-wall formed by the rigid Cβ FG loop. To investigate the significance of this conserved structure, we generated loop deletion (βΔFG) and βwt transgenic (tg) mice using the TCR β subunit of the N15 CTL. N15βwt and N15βΔFG H-2b animals have comparable numbers of thymocytes in S phase and manifest developmental progression through the CD4−CD8− double-negative (DN) compartment. N15βΔFG facilitates transition from DN to CD4+8+ double-positive (DP) thymocytes in recombinase activating gene (RAG)-2−/− mice, showing that pre-TCR function remains. N15βΔFG animals possess ∼twofold more CD8+ single-positive (SP) thymocytes and lymph node T cells, consistent with enhanced positive selection. As an altered Vα repertoire observed in N15βΔFG mice may confound the deletion's effect, we crossed N15αβ TCR tg RAG-2−/− with N15βΔFG tg RAG-2−/− H-2b mice to generate N15αβ RAG-2−/− and N15αβ.βΔFG RAG-2−/− littermates. N15αβ.βΔFG RAG-2−/− mice show an 8–10-fold increase in DP thymocytes due to reduced negative selection, as evidenced by diminished constitutive and cognate peptide-induced apoptosis. Compared with N15αβ, N15αβ.βΔFG T cells respond poorly to cognate antigens and weak agonists. Thus, the Cβ FG loop facilitates negative selection of thymocytes and activation of T cells.

scholarly journals Involvement of Prep1 in the αβ T-Cell Receptor T-Lymphocytic Potential of Hematopoietic Precursors

2005 ◽  
Vol 25 (24) ◽  
pp. 10768-10781 ◽  
Author(s):  
Dmitri Penkov ◽  
Patrizia Di Rosa ◽  
Luis Fernandez Diaz ◽  
Veronica Basso ◽  
Elisabetta Ferretti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fetal Liver ◽  
Physiological Role ◽  
Cell Receptor ◽  
Wild Type ◽  
Double Positive ◽  
Single Positive ◽  
Low Levels

ABSTRACT Prep1 is a homeodomain transcription factor that acts by dimerizing with Pbx. Since Prep1 null embryos die at gastrulation, we studied Prep1 i/i hypomorphic mice to study the physiological role of Prep1. A low percentage of homozygous Prep1 i/i mice survived at birth, and their postnatal functions could be investigated. Reduced Prep1 expression caused an abnormal thymic T-cell development: increased CD4− CD8− double-negative thymocytes, decrease in αβTCRhigh cells (cells with high levels of the αβΤ-cell receptor [αβTCR]) and CD4+ and CD8+ single-positive (SP) thymocytes, and increase in γδTCR cells. Peripheral lymphoid organs of Prep1 i/i mice contained fewer αβTCR mature T cells and more γδTCR T cells than wild-type littermates. Moreover, Prep1 i/i CD4+ CD8+ double-positive thymocytes underwent more apoptosis, and SP thymocytes proliferated less than control littermates. Mice that were lethally irradiated and then had Prep1 i/i fetal liver cells transplanted showed the same defects as the Prep1 i/i mice did. Among PBC family members, Pbx2 and very low levels of Pbx3 were observed in the thymi of wild-type mice. In Prep1 i/i mice, the level of Pbx2 protein was profoundly decreased, while for Pbx3 no definitive conclusion could be reached. Therefore, the deficient postnatal T-lymphocytic potential of the Prep1 hematopoietic progenitors depends on the combined, not compensated, absence of Prep1 and at least Pbx2.

scholarly journals The timing of TCRα expression critically influences T cell development and selection

2005 ◽  
Vol 202 (1) ◽  
pp. 111-121 ◽  
Author(s):  
Troy A. Baldwin ◽  
Michelle M. Sandau ◽  
Stephen C. Jameson ◽  
Kristin A. Hogquist
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Thymocyte Development ◽  
Double Positive ◽  
Thymic Development ◽  
Intestinal Intraepithelial Lymphocytes ◽  
Single Positive ◽  
Α Chain

Sequential rearrangement of the T cell receptor for antigen (TCR) β and α chains is a hallmark of thymocyte development. This temporal control is lost in TCR transgenics because the α chain is expressed prematurely at the CD4−CD8− double negative (DN) stage. To test the importance of this, we expressed the HYα chain at the physiological CD4+CD8+ double positive (DP) stage. The reduced DP and increased DN cellularity typically seen in TCR transgenics was not observed when the α chain was expressed at the appropriate stage. Surprisingly, antigen-driven selection events were also altered. In male mice, thymocyte deletion now occurred at the single positive or medullary stage. In addition, no expansion of CD8αα intestinal intraepithelial lymphocytes (IELs) was observed, despite the fact that HY transgenics have been used to model IEL development. Collectively, these data establish the importance of proper timing of TCR expression in thymic development and selection and emphasize the need to use models that most accurately reflect the physiologic process.

scholarly journals Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 510-518 ◽  
Author(s):  
Xiaoming Feng ◽  
Gregory C. Ippolito ◽  
Lifeng Tian ◽  
Karla Wiehagen ◽  
Soyoung Oh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transcriptional Regulator ◽  
Cell Receptor ◽  
Abnormal Development ◽  
Thymocyte Development ◽  
Naive T Cells ◽  
Central Tolerance ◽  
Naïve T Cells ◽  
Single Positive

Abstract Proper thymocyte development is required to establish T-cell central tolerance and to generate naive T cells, both of which are essential for T-cell homeostasis and a functional immune system. Here we demonstrate that the loss of transcription factor Foxp1 results in the abnormal development of T cells. Instead of generating naive T cells, Foxp1-deficient single-positive thymocytes acquire an activated phenotype prematurely in the thymus and lead to the generation of peripheral CD4+ T and CD8+ T cells that exhibit an activated phenotype and increased apoptosis and readily produce cytokines upon T-cell receptor engagement. These results identify Foxp1 as an essential transcriptional regulator for thymocyte development and the generation of quiescent naive T cells.

scholarly journals The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells

2007 ◽  
Vol 204 (8) ◽  
pp. 1945-1957 ◽  
Author(s):  
Takeshi Egawa ◽  
Robert E. Tillman ◽  
Yoshinori Naoe ◽  
Ichiro Taniuchi ◽  
Dan R. Littman
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cytotoxic T Cell ◽  
Thymocyte Development ◽  
Double Positive ◽  
Interleukin 7 ◽  
Genes Encoding ◽  
Single Positive

Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4−CD8− double-negative stage to the CD4+CD8+ double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4+ helper and CD8+ cytotoxic T cell lineages, respectively. Runx1-deficient CD4+ T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8+ mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells.

scholarly journals CD6 modulates thymocyte selection and peripheral T cell homeostasis

2016 ◽  
Vol 213 (8) ◽  
pp. 1387-1397 ◽  
Author(s):  
Marc Orta-Mascaró ◽  
Marta Consuegra-Fernández ◽  
Esther Carreras ◽  
Romain Roncagalli ◽  
Amado Carreras-Sureda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
Autoimmune Response ◽  
Effector Memory ◽  
Thymocyte Development ◽  
Double Positive

The CD6 glycoprotein is a lymphocyte surface receptor putatively involved in T cell development and activation. CD6 facilitates adhesion between T cells and antigen-presenting cells through its interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), and physically associates with the T cell receptor (TCR) at the center of the immunological synapse. However, its precise role during thymocyte development and peripheral T cell immune responses remains to be defined. Here, we analyze the in vivo consequences of CD6 deficiency. CD6−/− thymi showed a reduction in both CD4+ and CD8+ single-positive subsets, and double-positive thymocytes exhibited increased Ca2+ mobilization to TCR cross-linking in vitro. Bone marrow chimera experiments revealed a T cell–autonomous selective disadvantage of CD6−/− T cells during development. The analysis of TCR-transgenic mice (OT-I and Marilyn) confirmed that abnormal T cell selection events occur in the absence of CD6. CD6−/− mice displayed increased frequencies of antigen-experienced peripheral T cells generated under certain levels of TCR signal strength or co-stimulation, such as effector/memory (CD4+TEM and CD8+TCM) and regulatory (T reg) T cells. The suppressive activity of CD6−/− T reg cells was diminished, and CD6−/− mice presented an exacerbated autoimmune response to collagen. Collectively, these data indicate that CD6 modulates the threshold for thymocyte selection and the generation and/or function of several peripheral T cell subpopulations, including T reg cells.

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