scholarly journals TNF activation of NF-κB is essential for development of single-positive thymocytes

2016 ◽  
Vol 213 (8) ◽  
pp. 1399-1407 ◽  
Author(s):  
Louise V. Webb ◽  
Steven C. Ley ◽  
Benedict Seddon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Thymic Development ◽  
Survival And Development ◽  
Single Positive ◽  
Tcr Activation

NF-κB activation has been implicated at multiple stages of thymic development of T cells, during which it is thought to mediate developmental signals originating from the T cell receptor (TCR). However, the Card11–Bcl10–Malt1 (CBM) complex that is essential for TCR activation of NF-κB in peripheral T cells is not required for thymocyte development. It has remained unclear whether the TCR activates NF-κB independent of the CBM complex in thymocyte development or whether another NF-κB activating receptor is involved. In the present study, we generated mice in which T cells lacked expression of both catalytic subunits of the inhibitor of κB kinase (IKK) complex, IKK1 and IKK2, to investigate this question. Although early stages of T cell development were unperturbed, maturation of CD4 and CD8 single-positive (SP) thymocytes was blocked in mice lacking IKK1/2 in the T cell lineage. We found that IKK1/2-deficient thymocytes were specifically sensitized to TNF-induced cell death in vitro. Furthermore, the block in thymocyte development in IKK1/2-deficient mice could be rescued by blocking TNF with anti-TNF mAb or by ablation of TNFRI expression. These experiments reveal an essential role for TNF activation of NF-κB to promote the survival and development of single positive T cells in the thymus.

Functional and Molecular Analysis of Maturation of Thymocytes in Bcl10 or Malt1 Deficient Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3323-3323
Author(s):  
Philipp J. Jost ◽  
Uta Ferch ◽  
Stephanie Weiss ◽  
Stephanie Leeder ◽  
Olaf Gross ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Animals ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Single Positive ◽  
T Cell Selection ◽  
Deficient Mice

Abstract Development of immature T cells in the thymus requires signals through the clonotypic T cell receptor (TCR). Thymocytes expressing a functionally inactive or autoreactive TCR are deleted via apoptosis (negative selection). Thymocytes expressing a functionally active but not autoreactive TCR are selected through inhibition of cell death (positive selection). Deregulation of this process is likely to result in autoimmunity or lymphomagenesis of T cells. The intracellular mechanisms by which the balance between TCR-dependent survival and apoptosis are regulated are largely unknown. A central regulator of survival and apoptosis in the immune system is the transcription factor NF-κB. Activation of NF-κB in mature T-cells requires the adaptor proteins Bcl10 and Malt1. Using gene-targeted mice deficient for Bcl10 or Malt1, we show that Bcl10 and Malt1 are also required for TCR-induced NF-κB activation in immature T cells. Furthermore, to elucidate the process of T cell selection within the thymus, we have crossed Bcl10 or Malt1 deficient mice into mice with genetic backgrounds expressing defined TCR transgenes. Using specific peptide agonists of these TCR transgenes, we show that neither in vivo nor in vitro development into single positive (SP) CD4 or CD8 positive T cells is altered in Bcl10 or Malt1 deficient mice. Absolute numbers and ratio of SP T cells found within the thymus or in peripheral lymphnodes of transgenic animals are normal. These findings indicate that Bcl10 and Malt1 activate NF-κB in thymocytes but are dispensable for maturation of immature T cells in this model system.

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 The majority of postselection CD4+ single-positive thymocytes requires the thymus to produce long-lived, functional T cells.

1995 ◽  
Vol 181 (1) ◽  
pp. 235-245 ◽  
Author(s):  
R Dyall ◽  
J Nikolić-Zugić
Keyword(s):  
T Cells ◽  
T Cell ◽  
Control Point ◽  
Cell Receptor ◽  
Cross Linking ◽  
Final Maturation ◽  
Tumor Virus ◽  
Single Positive ◽  
Developmental Characteristics

We have previously isolated, and characterized in vitro, two subsets of CD4hi T cell receptor (TCR)hi single positive (SP) thymocytes: CD8- and CD8lo. In this report, we have analyzed phenotypic, functional, and developmental characteristics of these "late" CD4hi SP thymocyte subsets. The TCRhi phenotype and the elimination of T cells expressing TCR V beta segments reactive with endogenous mouse mammary tumor virus (MMTV) products suggested that both subsets had undergone positive and negative selection. CD8-4hi thymocytes were functional, as judged by their ability to: (a) induce lethal graft versus host disease (GVHD); (b) survive and expand in peripheral lymphoid organs; and (c) proliferate, rather than undergo apoptosis, in response to in vitro TCR cross-linking. By contrast, CD8lo4hi cells could not induce GVHD, were unable to expand (and perhaps even survive) in peripheral organs and underwent apoptosis upon TCR cross-linking. However, when reintroduced into the thymus, these cells matured into functional, long-lived CD8-4hi lymphocytes. These results document an obligatory requirement for the thymic microenvironment in the final maturation of the majority of CD4hi SP postselection thymocytes, and demonstrate the existence of a previously unrecognized control point in T cell development.

scholarly journals Identification of a DNA Segment Exhibiting Rearrangement Modifying Effects upon Transgenic δ-deleting Elements

1997 ◽  
Vol 186 (1) ◽  
pp. 91-100 ◽  
Author(s):  
Karen M. Janowski ◽  
Stephanie Ledbetter ◽  
Matthew S. Mayo ◽  
Richard D. Hockett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Recombination Frequency ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Cell Type ◽  
Reporter Construct ◽  
In Vitro Recombination ◽  
Recombination Assay

Control of the rearrangement and expression of the T cell receptor α and δ chains is critical for determining T cell type. The process of δ deletion is a candidate mechanism for maintaining separation of the α and δ loci. Mice harboring a transgenic reporter δ deletion construct show α/β T cell lineage–specific use of the transgenic elements. A 48-basepair segment of DNA, termed HPS1A, when deleted from this reporter construct, loses tight lineage-specific rearrangement control of transgenic elements, with abundant rearrangements of transgenic δ-deleting elements now in γ/δ T cells. Furthermore, HPS1A augments recombination frequency of extrachromosomal substrates in an in vitro recombination assay. DNA binding proteins recognizing HPS1A have been identified and are restricted to early B and T cells, during the time of active rearrangement of endogenous TCR and immunoglobulin loci. These data are consistent with δ deletion playing an important role in maintaining separate TCR α and δ loci.

scholarly journals Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1440-1447 ◽  
Author(s):  
Sophie M. Lehar ◽  
James Dooley ◽  
Andrew G. Farr ◽  
Michael J. Bevan
Keyword(s):  
T Cell ◽  
Stromal Cells ◽  
Notch Pathway ◽  
Cell Lineage ◽  
Thymocyte Development ◽  
Thymic Development ◽  
T Cell Progenitors ◽  
Notch Ligands ◽  
Immature Thymocytes

AbstractSignaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow–derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and γδ T-cell lineages.

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 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 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.

scholarly journals Requirement of CD3 Complex–associated Signaling Functions for Expression of Rearranged T Cell Receptor β VDJ Genes in Early Thymic Development

1998 ◽  
Vol 188 (9) ◽  
pp. 1669-1678 ◽  
Author(s):  
Andreas Würch ◽  
Judit Biro ◽  
Alexandre J. Potocnik ◽  
Ingrid Falk ◽  
Horst Mossmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Double Positive ◽  
Thymic Development ◽  
Cell Progression ◽  
Complex Signaling ◽  
Polypeptide Chains

During αβ thymocyte development, the clonotypic αβ–T cell receptor (TCR) is preceded by sequentially expressed immature versions of the TCR–CD3 complex: the pre-TCR, containing a clonotypic TCR-β chain and invariant pre-Tα, is expressed on pre-T cells before rearrangement of the TCR-α locus. Moreover, clonotype-independent CD3 complexes (CIC) appear on pro-T cells before VDJ rearrangements of TCR-β genes. The pre-TCR is known to mediate TCR-β selection, the prerequisite for maturation of CD4−8− double negative (DN) thymocytes to the CD4+8+ double positive stage. A developmental function of CIC has so far not been delineated. In mice single deficient and double deficient for CD3ζ/η and/or p56lck, we observe a pronounced reduction in the proportions of CD25+ DN thymocytes that express intracellular TCR-β chains. TCR-β transcripts are reduced in parallel with TCR-β polypeptide chains whereas no reduction in TCR-β locus rearrangements could be detected. Wild-type levels of TCR-β transcripts and of cells expressing TCR-β polypeptide chains are induced by treatment with anti-CD3ε mAb. The data suggest that the initial expression of rearranged TCR-β VDJ genes in pro-T cell to pre-T cell progression is dependent on CD3 complex signaling, and thus define a putative developmental function for CIC.

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