scholarly journals The Route of Early T Cell Development: Crosstalk between Epigenetic and Transcription Factors

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1074
Author(s):  
Veronica Della Chiara ◽  
Lucia Daxinger ◽  
Frank J. T. Staal
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Regulatory Networks ◽  
Developmental Stages ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Multipotent Progenitors ◽  
Epigenetic Regulators

Hematopoietic multipotent progenitors seed the thymus and then follow consecutive developmental stages until the formation of mature T cells. During this process, phenotypic changes of T cells entail stage-specific transcriptional programs that underlie the dynamic progression towards mature lymphocytes. Lineage-specific transcription factors are key drivers of T cell specification and act in conjunction with epigenetic regulators that have also been elucidated as crucial players in the establishment of regulatory networks necessary for proper T cell development. In this review, we summarize the activity of transcription factors and epigenetic regulators that together orchestrate the intricacies of early T cell development with a focus on regulation of T cell lineage commitment.

scholarly journals Essential Role of Survivin, an Inhibitor of Apoptosis Protein, in T Cell Development, Maturation, and Homeostasis

2003 ◽  
Vol 199 (1) ◽  
pp. 69-80 ◽  
Author(s):  
Zheng Xing ◽  
Edward M. Conway ◽  
Chulho Kang ◽  
Astar Winoto
Keyword(s):  
T Cells ◽  
T Cell ◽  
Developmental Stages ◽  
T Cell Development ◽  
Cell Development ◽  
Inhibitor Of Apoptosis ◽  
Proliferating Cells ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein

Survivin is an inhibitor of apoptosis protein that also functions during mitosis. It is expressed in all common tumors and tissues with proliferating cells, including thymus. To examine its role in apoptosis and proliferation, we generated two T cell–specific survivin-deficient mouse lines with deletion occurring at different developmental stages. Analysis of early deleting survivin mice showed arrest at the pre–T cell receptor proliferating checkpoint. Loss of survivin at a later stage resulted in normal thymic development, but peripheral T cells were immature and significantly reduced in number. In contrast to in vitro studies, loss of survivin does not lead to increased apoptosis. However, newborn thymocyte homeostatic and mitogen-induced proliferation of survivin-deficient T cells were greatly impaired. These data suggest that survivin is not essential for T cell apoptosis but is crucial for T cell maturation and proliferation, and survivin-mediated homeostatic expansion is an important physiological process of T cell development.

scholarly journals Towards Understanding & Uncovering New Key Players in T-Cell Development upon Aging

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2482-2482
Author(s):  
Hanane Boukarabila ◽  
Kalpana Nattamai ◽  
Medhanie Assmelash Mulaw ◽  
Hartmut Geiger
Keyword(s):  
T Cells ◽  
T Cell ◽  
Differentially Expressed Genes ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Thymic Involution ◽  
Total P

Aging-associated immune remodeling (AAIR) leads to an impaired ability to respond to vaccination and combat infections, and is due to many factors acting in concert. Several studies have linked the T-cell decline that occurs with age to thymic involution. However, there is novel and mounting evidence that also aged lymphoid-primed multipotent progenitors (LMPPs) are immune system intrinsic players in AAIR. However, very little is known on molecular and cellular mechanisms by which aging LMPPs could drive this AAIR phenomenon. Deciphering the underlying mechanisms is of crucial importance for developing new therapies to attenuate AAIR. Here, we present new data demonstrating the dysregulated pathways associated with aged LMPPs and the cellular changes in early thymic differentiation events in driving AAIR. To assess the T-lineage potential of aged LMPPs, we performed single cells ex-vivo OP9D assays using LMPPs (Lin-cKit+Sca1+CD34-Flt3hi) from aged (18-20 month-old) and young (8-10 week-old) C57BL/6 animals as controls. The frequencies of T-cell lineage potential in aged LMPPs and young LMPPs at the single cell level were very similar. This result was also validated in vivo by transplantation assays where 5000 aged or young LMPPs were injected into sub-lethally irradiated young recipients followed by T-cell lineage (CD4+ & CD8+) analysis in the peripheral blood (PB) at 4 weeks post transplantation (Mean; Y:12,75 vs A:16:23 % of total, p=0.46). However, aged LMPPs were associated with a dramatic disadvantage of PB T-cells at 4 weeks post injections (Mean; Y:9 vs A:2.3 % of total, p<0.0001) and in the development of all thymic stages of thymocytes, from early double negative stage CD4-CD8-(DN1) (Mean; Y:30 vs A:8 % of parent, p<0.0001) to double positive stage CD4+CD8+(DP) (Mean; Y:53 vs A:15 % of parent, p<0.0001), as well as single positive (SP) CD4+(Mean; Y:54 vs A:13 % of parent, p<0.0001) and CD8+(Mean; Y:45 vs A:10 % of parent, p<0.0001) thymocytes when intravenously transplanted in combination with 1:1 ratio of young LMPPs into young recipients. To overcome a potential homing to the thymus bias of aged LMPPs in competitive transplants, we performed intra-thymic injections of young and aged LMPPs with identical ratios into sub-lethally irradiated young recipients. The analysis of PB at 4 weeks post injections show a dramatic reduction of PB T-cells derived from aged LMPPs in comparison with young LMPPs (Mean; Y:14.8 vs A:8 % of total, p<0.0001). There was primarily a strong disadvantage towards generating DP stage (Mean; Y:46 vs A:28 % of parent, p<0.0001), suggesting that the intra-thymic injections indeed alleviated the dramatic decrease in the early thymocyte stage DN1 (Mean; Y:31 vs A:22 % of parent, p<0.05). This suggests that aged LMPPs confer a T-cell differentiation and maybe an additional homing to the thymus defect. We also performed RNA-Seq analyses on LMPPs from young and aged mice. Unsupervised hierarchical clustering of differentially expressed genes between young and aged LMPPs highlighted a clear dysregulation of only a few pathways that are involved in T-cell development such as Notch signaling. We next correlated our RNA-Seq data with other immunological signatures in attempt to look for more T-cell specific key factors that are differentially expressed between young and aged LMPPs. Importantly, the results show that the data from our RNA-Seq correlated with more than 400 immunological signatures among which 25 were most highly correlated. Interestingly, this correlation has allowed us to curate a list of the top 30 differentially expressed genes between young and aged LMPPs including T-cell specific transcription factors such as Satb1 and Foxo1. Altogether, our findings reveal that the T-cell immune decline that occurs with age is already imprinted in LMPPs within the bone marrow and translates into a dysregulation of signaling pathways that are directly related to T-cell development. Targeting these pathways could open up new perspectives in attenuating AAIR. Disclosures No relevant conflicts of interest to declare.

scholarly journals Functional definition of a transcription factor hierarchy regulating T cell lineage commitment

2020 ◽  
Vol 6 (31) ◽  
pp. eaaw7313 ◽  
Author(s):  
Laura Garcia-Perez ◽  
Farbod Famili ◽  
Martijn Cordes ◽  
Martijn Brugman ◽  
Marja van Eggermond ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Notch Signaling ◽  
Target Genes ◽  
T Cell Development ◽  
Cell Lineage ◽  
Specific Protein ◽  
Cell Development

T cell factor 1 (Tcf1) is the first T cell–specific protein induced by Notch signaling in the thymus, leading to the activation of two major target genes, Gata3 and Bcl11b. Tcf1 deficiency results in partial arrests in T cell development, high apoptosis, and increased development of B and myeloid cells. Phenotypically, seemingly fully T cell–committed thymocytes with Tcf1 deficiency have promiscuous gene expression and an altered epigenetic profile and can dedifferentiate into more immature thymocytes and non-T cells. Restoring Bcl11b expression in Tcf1-deficient cells rescues T cell development but does not strongly suppress the development of non-T cells; in contrast, expressing Gata3 suppresses their development but does not rescue T cell development. Thus, T cell development is controlled by a minimal transcription factor network involving Notch signaling, Tcf1, and the subsequent division of labor between Bcl11b and Gata3, thereby ensuring a properly regulated T cell gene expression program.

scholarly journals An enriched network motif family regulates multistep cell fate transitions with restricted reversibility

2018 ◽  
Author(s):  
Yujie Ye ◽  
Jordan Bailey ◽  
Chunhe Li ◽  
Tian Hong
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Cell Fate ◽  
Biological Systems ◽  
T Cell Development ◽  
Cell Lineage ◽  
Design Principles ◽  
Cell Development ◽  
Gene Circuit ◽  
Gene Regulatory

AbstractMultistep cell fate transitions with stepwise changes of transcriptional profiles are common to many developmental, regenerative and pathological processes. The multiple intermediate cell lineage states can serve as differentiation checkpoints or branching points for channeling cells to more than one lineages. However, mechanisms underlying these transitions remain elusive. Here, we explored gene regulatory circuits that can generate multiple intermediate cellular states with stepwise modulations of transcription factors. With unbiased searching in the network topology space, we found a motif family containing a large set of networks can give rise to four attractors with the stepwise regulations of transcription factors, which limit the reversibility of three consecutive steps of the lineage transition. We found that there is an enrichment of these motifs in a transcriptional network controlling the early T cell development, and a mathematical model based on this network recapitulates multistep transitions in the early T cell lineage commitment. By calculating the energy landscape and minimum action paths for the T cell model, we quantified the stochastic dynamics of the critical factors in response to the differentiation signal with fluctuations. These results are in good agreement with experimental observations and they suggest the stable characteristics of the intermediate states in the T cell differentiation. These dynamical features may help to direct the cells to correct lineages during development. Our findings provide general design principles for multistep cell linage transitions and new insights into the early T cell development. The network motifs containing a large family of topologies can be useful for analyzing diverse biological systems with multistep transitions.Author summaryThe functions of cells are dynamically controlled in many biological processes including development, regeneration and disease progression. Cell fate transition, or the switch of cellular functions, often involves multiple steps. The intermediate stages of the transition provide the biological systems with the opportunities to regulate the transitions in a precise manner. These transitions are controlled by key regulatory genes of which the expression shows stepwise patterns, but how the interactions of these genes can determine the multistep processes were unclear. Here, we present a comprehensive analysis on the design principles of gene circuits that govern multistep cell fate transition. We found a large network family with common structural features that can generate systems with the ability to control three consecutive steps of the transition. We found that this type of networks is enriched in a gene circuit controlling the development of T lymphocyte, a crucial type of immune cells. We performed mathematical modeling using this gene circuit and we recapitulated the stepwise and irreversible loss of stem cell properties of the developing T lymphocytes. Our findings can be useful to analyze a wide range of gene regulatory networks controlling multistep cell fate transitions.

scholarly journals Id proteins suppress E2A-driven innate-like T cell development prior to TCR selection

2017 ◽  
Author(s):  
Sumedha Roy ◽  
Amanda J. Moore ◽  
Cassandra Love ◽  
Anupama Reddy ◽  
Deepthi Rajagopalan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Large Population ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Inkt Cells ◽  
Tcr Signaling ◽  
Γδt Cells ◽  
Id Proteins

AbstractId proteins have been shown to promote the differentiation of conventional αβ and γδT cells, and to suppress the expansion of invariant Natural Killer T (iNKT) cells and innate-like γδNKT within their respective cell lineages. However, it remains to be determined whether Id proteins regulate lineage specification in developing T cells that give rise to these distinct cell fates. Here we report that in the absence of Id2 and Id3 proteins, E2A prematurely activates genes critical for the iNKT cell lineage prior to TCR expression. Enhanced iNKT development in Id3-deficient mice lacking γδ NKT cells suggests that Id3 regulates the lineage competition between these populations. RNA-Seq analysis establishes E2A as the transcriptional regulator of both iNKT and γδNKT development. In the absence of pre-TCR signaling, Id2/Id3 deletion gives rise to a large population of iNKT cells and a unique innate-like DP population, despite the block in conventional αβ T cell development. The transcriptional profile of these unique DP cells reflects enrichment of innate-like signature genes, including PLZF (Zbtb16) and Granzyme A (Gzma). Results from these genetic models and genome-wide analyses suggest that Id proteins suppress E2A-driven innate-like T cell programs prior to TCR selection to enforce predominance of conventional T cells.

Rac1 and Rac2 GTPases Play Redundant but Critical Role in T-Cell Development and Survival.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3304-3304
Author(s):  
Fukun Guo ◽  
David Hildeman ◽  
David A. Williams ◽  
Yi Zheng
Keyword(s):  
T Cells ◽  
T Cell ◽  
Developmental Stages ◽  
Critical Role ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Subsets ◽  
Actin Dynamics ◽  
Hematopoietic Stem ◽  
Apoptosis Rate

Abstract The Rac subfamily GTPases of the Rho family have been implicated in the control of actin dynamics, cell proliferation, apoptosis, adhesion and migration of many blood cell types including hematopoietic stem/progenitors, neutrophils and macrophages, but their role in T cell development remains poorly understood. T cells from the Rac2 deficient mice appear to mostly undergo normal development, whereas previous constitutively active mutant Rac2 or Rac1 overexpression studies suggest Rac GTPases are required for CD4+ and CD8+ T cell maturation. Using conditional gene targeting, we have achieved specific deletion of Rac1 or Rac1 together with Rac2 in the T cell lineage by cross-breeding the Lck-Cre transgenic mice with the Rac1flox/flox mice that contain a pair of loxP sites sandwiching the exon 1 sequences of Rac1 or the Rac1flox/flox;Rac2−/− mice. We show that similar to Rac2 deficiency, inactivation of Rac1 alone had little effect on various developmental stages of T cells in the animal. However, deletion of both Rac1 and Rac2 significantly affected both the immature CD4−CD8− (2.3 fold increase) and CD4+CD8+ (13% decrease) populations in the mouse thymus and the mature CD4+ and CD8+ populations in the thymus and spleen (Table). These developmental defects are associated with proliferation defects of thymocytes and splenocytes in response to ConA or PMA/ionomycin stimulation and deficient survival of various T cell populations at different developmental stages (Table). Together, these data show that Rac1 and Rac2 play overlapping and obligatory roles in T-cell development and serve as important cell survival regulators at various stages. Table. Frequency and apoptosis rate of different T-cell subsets in thymocytes and splenocytes T cell subsets WT (n=10) Rac1−/− (n=6) Rac1−/−Rac2−/−(n=6) Total thymocyte number (×106) 101.3±30.0 98.0±25.0 44.7±25.5 CD4−CD8− thymocyte frequency (%) 5.5±1.9 4.5±0.7 12.7±4.3 apoptosis rate (%) 20.1±2.2 15.0±1.3 CD4+CD8+ thymocyte frequency (%) 76.2±3.2 77.3±4.1 66.2±5.4 apoptosis rate (%) 18.8±4.3 27.9±2.8 CD4+ thymocyte frequency (%) 14.5±3.4 14.4±2.4 7.9±2.3 apoptosis rate (%) 13.3±2.3 21.5±4.5 CD8+ thymocyte frequency (%) 3.9±1.2 3.8±1.0 13.2±2.2 apoptosis rate (%) 12.5±2.2 8.8±1.1 Total splenocyte number (×106) 60.4±21.8 62.0±13.0 51.1±28.9 CD4+TCRβ+ splenocyte frequency (%) 9.7±2.2 8.0±2.3 3.2±1.1 apoptosis rate (%) 15.1±3.1 27.5±6.9 CD8+TCRβ+ splenocyte frequency (%) 3.2±0.8 2.4±0.9 0.6±0.4 apoptosis rate (%) 13.1±3.0 24.5±6.4

scholarly journals Tle corepressors are differentially partitioned to instruct CD8+ T cell lineage choice and identity

2018 ◽  
Vol 215 (8) ◽  
pp. 2211-2226 ◽  
Author(s):  
Shaojun Xing ◽  
Peng Shao ◽  
Fengyin Li ◽  
Xudong Zhao ◽  
Wooseok Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cd8 T Cell ◽  
Double Positive ◽  
Mhc I ◽  
Transcriptional Corepressors ◽  
Dose Dependent

Tle/Groucho proteins are transcriptional corepressors interacting with Tcf/Lef and Runx transcription factors, but their physiological roles in T cell development remain unknown. Conditional targeting of Tle1, Tle3 and Tle4 revealed gene dose–dependent requirements for Tle proteins in CD8+ lineage cells. Upon ablating all three Tle proteins, generation of CD8+ T cells was greatly diminished, largely owing to redirection of MHC-I–selected thymocytes to CD4+ lineage; the remaining CD8-positive T cells showed aberrant up-regulation of CD4+ lineage-associated genes including Cd4, Thpok, St8sia6, and Foxp3. Mechanistically, Tle3 bound to Runx-occupied Thpok silencer, in post-selection double-positive thymocytes to prevent excessive ThPOK induction and in mature CD8+ T cells to silence Thpok expression. Tle3 also bound to Tcf1-occupied sites in a few CD4+ lineage-associated genes, including Cd4 silencer and St8sia6 introns, to repress their expression in mature CD8+ T cells. These findings indicate that Tle corepressors are differentially partitioned to Runx and Tcf/Lef complexes to instruct CD8+ lineage choice and cooperatively establish CD8+ T cell identity, respectively.

scholarly journals Aberrant T cell differentiation in the absence of Dicer

2005 ◽  
Vol 202 (2) ◽  
pp. 261-269 ◽  
Author(s):  
Stefan A. Muljo ◽  
K. Mark Ansel ◽  
Chryssa Kanellopoulou ◽  
David M. Livingston ◽  
Anjana Rao ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Lineage ◽  
Interferon Γ ◽  
Cell Development ◽  
Conditional Allele ◽  
Microrna Processing

Dicer is an RNaseIII-like enzyme that is required for generating short interfering RNAs and microRNAs. The latter have been implicated in regulating cell fate determination in invertebrates and vertebrates. To test the requirement for Dicer in cell-lineage decisions in a mammalian organism, we have generated a conditional allele of dicer-1 (dcr-1) in the mouse. Specific deletion of dcr-1 in the T cell lineage resulted in impaired T cell development and aberrant T helper cell differentiation and cytokine production. A severe block in peripheral CD8+ T cell development was observed upon dcr-1 deletion in the thymus. However, Dicer-deficient CD4+ T cells, although reduced in numbers, were viable and could be analyzed further. These cells were defective in microRNA processing, and upon stimulation they proliferated poorly and underwent increased apoptosis. Independent of their proliferation defect, Dicer-deficient helper T cells preferentially expressed interferon-γ, the hallmark effector cytokine of the Th1 lineage.

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.

Sign in / Sign up

Export Citation Format

Share Document