Cell-fate decisions in early T cell development: regulation by cytokine receptors and the pre-TCR

1999 ◽  
Vol 11 (1) ◽  
pp. 23-37 ◽  
Author(s):  
Mariëlle C. Haks ◽  
Mariëtte A. Oosterwegel ◽  
Bianca Blom ◽  
Hergen M. Spits ◽  
Ada M Kruisbeek
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cytokine Receptors ◽  
Cell Fate Decisions ◽  
Development Regulation

The Histone Acetyltransferase CBP Is Essential for Conventional T Cell Development.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2294-2294
Author(s):  
Tomofusa Fukuyama ◽  
Fayçal Boussouar ◽  
Lawryn H. Kasper ◽  
Jan M. van Deursen ◽  
Paul K. Brindle
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Chemokine Receptors ◽  
Fas Ligand ◽  
T Cell Development ◽  
Cell Development ◽  
Mutant Mice ◽  
Effector Memory ◽  
Creb Binding Protein ◽  
Cell Fate Decisions

Abstract Defining the epigenetic mechanisms (e.g. chromatin modifications) that underlie T cell fate decisions is a major challenge. The transcriptional coactivators CREB binding protein (CBP) and the closely related p300 comprise a two-member family of histone/protein acetyltransferases that interact with over 50 T lymphocyte-essential transcriptional regulators. Rather than having distinct regulatory roles, CBP and p300 are often thought to confer utilitarian transactivation and histone modifying functions to transcription factors that mediate T cell fate. In contrast to this view, we show here that CBP acts uniquely in conventional T cell development. Inactivation of CBP, but not p300, starting at the double negative stage of T cell development yielded thymocytes with partial activation of an effector/memory- or innate-T cell program. CD8SP thymocytes from CBP mutant mice expressed genes that define professional CD8 cells such as Il-2/Il-15 receptor β chain, granzyme A, interferon γ (Ifnγ), Fas ligand, perforin, and the chemokine receptors Ccr5, and Cxcr3. CD4SP thymocytes from CBP mutant mice also expressed effector genes such as Ifnγ, Il-4, and Ccr5. In addition, CD8SP and CD4SP thymocytes from CBP mutant mice produced Ifnγ protein when the cells were stimulated with phorbol ester and ionomycin. Mechanistically, loss of CBP acted cell non-autonomously to induce the expression of the CD8 T cell master regulatory transcription factor eomesodermin (Eomes). This suggests that CBP in thymocytes or T cells controls an extracellular factor that helps demarcate conventional naïve T cell development in the thymus from effector/memory T cell differentiation in the periphery.

scholarly journals The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3618-3623 ◽  
Author(s):  
Lizi Wu ◽  
Ivan Maillard ◽  
Makoto Nakamura ◽  
Warren S. Pear ◽  
James D. Griffin
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
Marginal Zone ◽  
Gene Dosage ◽  
Fetal Liver ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Fate Decisions ◽  
Perinatal Lethality

Abstract Signaling mediated by various Notch receptors and their ligands regulates diverse biological processes, including lymphoid cell fate decisions. Notch1 is required during T-cell development, while Notch2 and the Notch ligand Delta-like1 control marginal zone B (MZB) cell development. We previously determined that Mastermind-like (MAML) transcriptional coactivators are required for Notchinduced transcription by forming ternary nuclear complexes with Notch and the transcription factor CSL. The 3 MAML family members (MAML1-MAML3) are collectively essential for Notch activity in vivo, but whether individual MAMLs contribute to the specificity of Notch functions is unknown. Here, we addressed this question by studying lymphopoiesis in the absence of the Maml1 gene. Since Maml1−/− mice suffered perinatal lethality, hematopoietic chimeras were generated with Maml1−/−, Maml1+/−, or wild-type fetal liver progenitors. Maml1 deficiency minimally affected T-cell development, but was required for the development of MZB cells, similar to the phenotype of Notch2 deficiency. Moreover, the number of MZB cells correlated with Maml1 gene dosage. Since all 3 Maml genes were expressed in MZB cells and their precursors, these results suggest that Maml1 is specifically required for Notch2 signaling in MZB cells.

scholarly journals Multiple extrathymic precursors contribute to T-cell development with different kinetics

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1137-1144 ◽  
Author(s):  
Namita Saran ◽  
Marcin Łyszkiewicz ◽  
Jens Pommerencke ◽  
Katrin Witzlau ◽  
Ramin Vakilzadeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Precursor ◽  
Lineage Differentiation ◽  
Multipotent Cells ◽  
Kinetics Of

Abstract T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches.

Notch Activation Converts B Cells into a T Cell Fate at the Earliest Stages of B Cell Committed Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3151-3151
Author(s):  
Jalal Taneera ◽  
Emma Smith ◽  
Mikael Sigvardsson ◽  
Emil Hansson ◽  
Urban Lindahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Stage ◽  
Cell Commitment ◽  
Notch Activation

Abstract Notch activation has been suggested to promote T cell development at the expense of B cell commitment at the level of a common lymphoid progenitor prior to B cell commitment. Here, we explored the possibility that Notch activation might be able to switch the fate of already committed B cell progenitors towards T cell development upon Notch activation. To address this we overexpressed constitutively activated Notch-3 (N3IC) in B cell progenitors purified from transgenic mice in which human CD25 is expressed under control of the λ5 promoter. Strikingly, whereas untransduced and control transduced B220+λ5+CD3− B cell progenitors gave rise exclusively to B cells, CD4+ and CD8+ T cells but no B cells were derived from N3IC-transduced cells when transplanted into sublethally irradiated NOD-SCID mice. Gene expression profiling demonstrated that untransduced B220+ λ5+CD3− B cell progenitors expressed λ5 and CD19 but not the T cell specific genes GATA-3, lck and pTα, whereas CD3+ T cells derived from N3IC-transduced B220+λ5+CD3−cells failed to express λ5 and CD19, but were positive for GATA-3, lck and pTα expression as well as a and b T cell rearrangement. Furthermore, DJ rearrangements were detected at very low levels in CD3+ cells isolated from normal non-transduced BM, but were more abundant in the N3IC-transduced CD3+ BM cells. Noteworthy, N3IC-transduced B220+λ5+CD3−CD19+ proB cell progenitors failed to generate B as well as T cells, whereas N3IC-transduced B220+λ5+CD3−CD19− pre-proB cells produced exclusively T cells, even when evaluated at low cell numbers. In conclusion Notch activation can switch committed B cell progenitors from a B cell to a T cell fate, but this plasticity is lost at the Pro-B cell stage, upon upregulation of CD19 expression.

scholarly journals Asymmetric cell division during T cell development controls downstream fate

2015 ◽  
Vol 210 (6) ◽  
pp. 933-950 ◽  
Author(s):  
Kim Pham ◽  
Raz Shimoni ◽  
Mirren Charnley ◽  
Mandy J. Ludford-Menting ◽  
Edwin D. Hawkins ◽  
...  
Keyword(s):  
Cell Division ◽  
T Cell ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Clones ◽  
Fate Determinants ◽  
Cell Fate Determinants ◽  
Selection Stage

During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal.

scholarly journals ATP-dependent chromatin remodeling in T cells1This article is part of Special Issue entitled Asilomar Chromatin and has undergone the Journal’s usual peer review process.

2012 ◽  
Vol 90 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Andrea L. Wurster ◽  
Michael J. Pazin
Keyword(s):  
Gene Regulation ◽  
T Cell ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Peer Review Process ◽  
T Cell Development ◽  
Cell Development ◽  
Compare And Contrast ◽  
Cell Gene ◽  
Present Understanding

One of the best studied systems for mammalian chromatin remodeling is transcriptional regulation during T cell development. The variety of these studies have led to important findings in T cell gene regulation and cell fate determination. Importantly, these findings have also advanced our knowledge of the function of remodeling enzymes in mammalian gene regulation. First we briefly present biochemical and cell-free analysis of 3 types of ATP dependent remodeling enzymes (SWI/SNF, Mi2, and ISWI) to construct an intellectual framework to understand how these enzymes might be working. Second, we compare and contrast the function of these enzymes during early (thymic) and late (peripheral) T cell development. Finally, we examine some of the gaps in our present understanding.

scholarly journals Human Delta Like 1-Expressing Human Mesenchymal Stem Cells Promote Human T Cell Development and Antigen-Specific Response in Humanized NOD/SCID/IL-2Rgnull (NSG) Mice

2021 ◽  
Author(s):  
Ki-Young Lee ◽  
Do Hee Kwon ◽  
Jae Berm Park ◽  
Joo Sang Lee ◽  
Sung Joo Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Specific Response ◽  
Cell Fate Decisions ◽  
Nsg Mice ◽  
Human T Cells

Abstract Human delta-like 1 (hDlk1) is known to be able to regulate cell fate decisions duringhematopoiesis. Mesenchymal stem cells (MSCs) are known to exhibit potentimmunomodulatory roles in a variety of diseases. Herein, we investigated in vivofunctions of hDlkl1-hMSCs and hDlk1+hMSCs in T cell development and T cell responseto viral infection in humanized NOD/SCID/IL-2Rγnull (NSG) mice. Co-injection ofhDlk1-hMSC with hCD34+ cord blood (CB) cells into the liver of NSG mice markedlysuppressed the development of human T cells. In contrast, co-injection of hDlk1+hMSCwith hCD34+ CB cells into the liver of NSG dramatically promoted the development ofhuman T cells. Human T cells developed in humanized NSG mice represent markedlydiverse in terms of TCR Vβ usages, functionally active, and the restriction to human MHCmolecules. Upon challenge with Epstein-Barr virus (EBV), EBV-specific hCD8+ T cellsin humanized NSG mic were effectively mounted with phenotypically activated T cellspresented as hCD45+hCD3+hCD8+hCD45RO+hHLA-DR+ T cells, suggesting thatantigen-specific T cell response was induced in the humanized NSG mice. Taken together,our data suggest that the hDlk1-expressing MSCs can effectively promote thedevelopment of human T cells and immune response to exogenous antigen in humanizedNSG mice. Thus, the humanized NSG model might have potential advantages for thedevelopment of therapeutics targeting infectious diseases in the future.

The Role of E Protein Heterodimer Partner Switching in Determining Chromatin Landscape and T Cell Fate Commitment in Mouse Early T Cell Development

2018 ◽  
Vol 64 ◽  
pp. S109
Author(s):  
Xun Wang ◽  
Peng He ◽  
Brian Williams ◽  
Jonas Ungerbäck ◽  
Maile Romero-Wolf ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
E Protein

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.

Sign in / Sign up

Export Citation Format

Share Document