Notch1 Deficiency Dissociates the Intrathymic Development of Dendritic Cells and T Cells

Thymic dendritic cells (DCs) form a discrete subset of bone marrow (BM)-derived cells, the function of which is to mediate negative selection of autoreactive thymocytes. The developmental origin of thymic DCs remains controversial. Although cell transfer studies support a model in which T cells and thymic DCs develop from the same intrathymic pluripotential precursor, it remains possible that these two types of cells develop from independent intrathymic precursors. Notch proteins are cell surface receptors involved in the regulation of cell fate specification. We have recently reported that T cell development in inducible Notch1-deficient mice is severely impaired at an early stage, before the expression of T cell lineage markers. To investigate whether development of thymic DCs also depends on Notch1, we have constructed mixed BM chimeric mice. We report here that thymic DC development from Notch1−/− BM precursors is absolutely normal (in terms of absolute number and phenotype) in this competitive situation, despite the absence of Notch1−/− T cells. Furthermore, we find that peripheral DCs and Langerhans cells are also not affected by Notch1 deficiency. Our results demonstrate that the development of DCs is totally independent of Notch1 function, and strongly suggest a dissociation between intrathymic T cell and DC precursors.

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Eto2/MTG16 Regulates E-Protein Activity and Subset Specification in Dendritic Cell Development

Blood ◽

10.1182/blood.v120.21.1229.1229 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1229-1229

Author(s):

Hiyaa Singhee Ghosh ◽

Kang Liu ◽

Scott Hiebert ◽

Boris Reizis

Keyword(s):

Dendritic Cells ◽

Transcription Factors ◽

T Cell ◽

Dendritic Cell ◽

Cell Fate ◽

Cell Lineage ◽

Transcriptional Regulators ◽

E Proteins ◽

E Protein

Abstract Abstract 1229 Eto-family proteins were first discovered as translocation fusion in AML1 (Runx1), a gene most frequently disrupted in human leukemia. Of the translocations that disrupt the AML1 gene in leukemia, Eto1(MTG8)/AML1 translocation accounts for ∼15% of Acute Myeloid Leukemia (AML). The Eto-family proteins function as transcriptional co-repressors that bind to DNA-binding transcription factors to regulate their target genes. Eto2 (MTG16) is an Eto-family member implicated in secondary or therapy-related AML, although recent reports provide evidence for Eto2/MTG16 translocations in de novo AML as well. Furthermore, recent studies have highlighted a role for MTG16 in HSC self renewal and T cell lineage specification, indicating its emerging role overall in hematopoiesis. The co-repressor function of Eto for E-proteins has been described previously in the context of Eto/AML1 fusion proteins. E-proteins are a class of basic-helix-loop-helix (bHLH) transcription factors that play an important role in hematopoiesis. Among the E-protein family, the role of E2A has been extensively studied in B and T cell development. Recently, our lab discovered the specific requirement of the E-protein E2-2 in the development of Plasmacytoid Dendritic Cells (pDC). pDC are the professional interferon producing (IPC) cells of our immune system important in anti-viral, anti-tumor and auto-immunity. pDC are a subtype of the antigen-presenting classical Dendritic Cells (cDC) with distinct structural and functional properties. Recently, we demonstrated that the putative cell fate plasticity of pDC was a direct manifestation of continuous E2-2 function. Using pDC-reporter mice in which E2-2 could be inducibly deleted from mature pDC we showed that the continuous expression of E2-2 was required to prevent the conversion of pDC to cDC. Here we report our current studies that investigate the molecular players underlying the E2-2 orchestrated genetic program for pDC cell fate decision and maintenance. Analyzing the transcriptome of the transitioning pDC, we have identified MTG16 as an important player in the fine regulation of DC lineage decisions. Using knock-out and chimeric mice, progenitor studies, promoter and biochemical analyses, we demonstrate MTG16 as an important E2-2 corepressor, promoting E2-2 mediated genetic program. We report that in order to facilitate the pDC cell fate, MTG16 enables E2-2 to suppress the cDC gene expression program, by negatively regulating the E-protein inhibitor Id2. The cell-fate conversion through deletion or overexpression of lineage-deciding transcriptional regulators has been described previously for B- and T cells. Theseh studies highlight the susceptibility of blood cells to aberrant functions of crucial transcriptional regulators, potentially leading to pathologic conditions. Therefore, understanding the interrelationship between the various genetic regulators that control lineage decisions and cell-fate plasticity is cardinal to accurate diagnosis and therapy for hematopoietic pathologies. Our study provides the first evidence for a physiological role of E-protein/Eto-protein interaction in dendritic cell lineage decision. Disclosures: No relevant conflicts of interest to declare.

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TOR Complex 1 and TOR Complex 2 Differentially Regulate Effector and Regulatory T Cell Differentiation

Blood ◽

10.1182/blood.v112.11.675.675 ◽

2008 ◽

Vol 112 (11) ◽

pp. 675-675 ◽

Cited By ~ 1

Author(s):

Greg M Delgoffe ◽

Thomas P. Kole ◽

Yan Zheng ◽

Bo Xiao ◽

Paul F. Worley ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Fate ◽

T Cell Activation ◽

Cell Activation ◽

Cell Lineage ◽

Lineage Commitment ◽

Th2 Cells ◽

Double Positive

Abstract Effector T cell lineage commitment is determined by the integration of multiple and sometimes opposing signals. Our lab has identified mTOR, an evolutionarily conserved serine/threonine kinase, as a crucial protein dictating the outcome of T cell fate in response to antigen. To do this we utilized a Cre-lox system to conditionally delete mTOR in T cells. In such mice, although mTOR is deleted in the double-positive stage, lymphocyte populations in the spleen and the periphery are comparable to wild-type mice. T cells lacking mTOR proliferate more slowly but secrete appropriate levels of IL-2 upon initial stimulation. However, such cells fail to differentiate into Th1, Th2 or Th17 effector T cells under the appropriate skewing conditions. This failure to differentiate is the result of decreases in appropriate STAT activation and the concomitant lack of upregulation in lineage specific transcription factors. Notably, under normally activating conditions, T cells lacking mTOR preferentially differentiate into Foxp3+ regulatory cells. Supporting this observation, mTOR deficient T cells display hyperactive Smad3 activation, even in the absence of exogenous TGF-β. mTOR signals through two known signaling complexes, TORC1 and TORC2. TORC1 contains Rheb, mTOR, GβL, and raptor, while TORC2 contains mSin1, mTOR, GβL, and rictor. In order to determine the specific role of TORC1 in T cell lineage commitment we conditionally deleted Rheb in T cells. Upon activation such cells fail to phosphorylate the TORC1 substrate S6K-1 while demonstrating normal TORC2 activity. As was the case for the mTOR−/− T cells, Rheb−/− T cells fail to differentiate into Th1 and Th17 cells when skewed in vitro. However, unlike mTOR−/− T cells, the Rheb deficient T cells are capable of becoming Th2 cells. In spite of lacking TORC1 activity, T cells lacking Rheb do not spontaneously develop into Foxp3+ cells. Such observations implicate a specific and novel role for Rheb in regulating T cell lineage commitment. Overall, our data identify mTOR as a regulator of T cell lineage commitment through which TORC1 and TORC2 signaling differentially regulate T cell fate. These findings support a novel paradigm whereby T cell activation induces a default pathway of differentiation to regulatory T cells and that TORC2 signaling is required to divert differentiation to appropriately programmed effector lineages.

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Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment

Blood ◽

10.1182/blood-2005-02-0496 ◽

2005 ◽

Vol 106 (10) ◽

pp. 3498-3506 ◽

Cited By ~ 66

Author(s):

Magda De Smedt ◽

Inge Hoebeke ◽

Katia Reynvoet ◽

Georges Leclercq ◽

Jean Plum

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cord Blood ◽

Notch Signaling ◽

Progenitor Cells ◽

Negative Impact ◽

Butyl Ester ◽

Cell Lineage ◽

Cord Blood Cd34

AbstractNotch receptors are involved in lineage decisions in multiple developmental scenarios, including hematopoiesis. Here, we treated hybrid human-mouse fetal thymus organ culture with the γ-secretase inhibitor 7 (N-[N-(3,5-difluorophenyl)-l-alanyl]-S-phenyl-glycine t-butyl ester) (DAPT) to establish the role of Notch signaling in human hematopoietic lineage decisions. The effect of inhibition of Notch signaling was studied starting from cord blood CD34+ or thymic CD34+CD1-, CD34+CD1+, or CD4ISP progenitors. Treatment of cord blood CD34+ cells with low DAPT concentrations results in aberrant CD4ISP and CD4/CD8 double-positive (DP) thymocytes, which are negative for intracellular T-cell receptor β (TCRβ). On culture with intermediate and high DAPT concentrations, thymic CD34+CD1- cells still generate aberrant intracellular TCRβ- DP cells that have undergone DJ but not VDJ recombination. Inhibition of Notch signaling shifts differentiation into non-T cells in a thymic microenvironment, depending on the starting progenitor cells: thymic CD34+CD1+ cells do not generate non-T cells, thymic CD34+CD1- cells generate NK cells and monocytic/dendritic cells, and cord blood CD34+Lin- cells generate B, NK, and monocytic/dendritic cells in the presence of DAPT. Our data indicate that Notch signaling is crucial to direct human progenitor cells into the T-cell lineage, whereas it has a negative impact on B, NK, and monocytic/dendritic cell generation in a dose-dependent fashion.

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Donor Plasmacytoid Dendritic Cells Home to the Thymus of the Transplant Recipient and Limit Graft Versus Host Diseases through Production of Vasoactive Intestinal Polypeptide

Blood ◽

10.1182/blood-2018-99-119172 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4518-4518

Author(s):

Yitong Wang ◽

Yiwen Li ◽

Jianming Li ◽

Jingxia Li ◽

Edmund K. Waller

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Research Funding ◽

Negative Selection ◽

Inflammatory Factor ◽

Graft Versus Host ◽

Donor T Cells ◽

Selection Of

Abstract Introduction: In allogeneic hematopoietic stem cell transplant (AHSCT), donor T cells promote hematopoietic engraftment, reconstitute T-cell immunity and mediate potent beneficial antitumor effects, such as graft versus leukemia (GVL) as well as detrimental graft-versus-host disease (GVHD). We have shown that purified bone marrow pDC to a donor graft composed of purified HSC and T cells significantly improved long-term leukemia-free survival without increasing the risk of GVHD (Lu BLOOD 2012). Vasoactive intestinal peptide (VIP) is a neuropeptide/neurotransmitter, which acts as a major anti-inflammatory factor in animal models of inflammatory and autoimmune diseases. VIP is produced by T cells and dendritic cells under conditions of inflammation (Li Cancer Research 2016). VIP-signaling, thus represents a newly appreciated co-inhibitory pathway involved in T cell activation and expansion and persistence of antigen-specific T cells, but the role of VIP produced by donor dendritic cells in allo-BMT is unclear. Our previous data has shown that production of VIP in pDC improves survival in a murine allo-BMT model. Since the thymus plays a critical role in regenerating naive T cells in which allo-reactive donor T cells undergoes central deletion. We hypothesized that donor pDCs that home to thymus modulate the negative selection of allo-reactive T cells and iTreg production through VIP signaling. Methods and Results: Our previous data has shown that the mice receiving HSC, T cells and WT pDC had a significantly higher survival (71%) compared to those receiving VIP-KO pDC (31%). On day 15 after transplant, recipients of WT pDC, VIP-KO pDC and no pDC developed ~98% chimerism, without significant differences among the three groups. Local production of VIP in pDC inhibited activation and Th1 immune polarization of donor T cells. Recipient spleens were harvested on day 15 after transplant for analysis of cytokine production by donor T cells. The percentage of CD8+ donor T cells producing IL17 was significantly higher in recipients of VIP-KO pDC compared to recipients of WT-pDC (Fig 2.A-B). The ratio of foxp3+ CD4+ donor T-reg to IL17+ CD4+ T cells from recipients of WT pDC was almost 3 times higher than the recipients of VIP-KO pDC (Fig 2.C-D). To visualize production of VIP by donor pDC, B10.BR mice were transplanted with 5,000 stem cells, 1M T cells and 50,000 pDCs from VIP-GFP (VIP promoter and GFP reporter) or GFP mice. On day 7 post-transplant, the thymus was examined with confocal microscopy with GFP (green), anti-PDCA-1-Alexa Fluor 568 (red) and DAPI (blue). A superimposed profile of the thymus showed that donor GFP pDCs homed to thymus (Fig.2-A), and that donor pDC in the recipient thymus produced VIP (Fig.2-B). Conclusion: Expression of VIP in donor pDCs inhibited activation and Th17 immune polarization of donor CD8+ T cells after allo-BMT. Foxp3+ expression tended to be higher among CD4+ donor T cells from recipients of WT pDCs compared with recipients of VIP-KO pDCs. Thus, VIP-producing donor pDC in thymus could be very critical to contribute to negative selection of allo-reactive donor T cell or facilitate the generation of Foxp3+ nTreg. This data supported a new mechanism by which GvHD maybe regulated and central tolerance maintained. Ongoing experiments aim at defining the role of VIP production in the thymus by donor pDC in positive and negative T cell selection. Disclosures Waller: Celldex: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership; Kalytera: Consultancy; Pharmacyclics: Other: Travel Expenses, EHA, Research Funding.

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Diagnostic 2-Gene Classifier in Early-Stage Mycosis Fungoides: A Retrospective Multicenter Study

Blood ◽

10.1182/blood-2019-122031 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2772-2772

Author(s):

Pia Rude Nielsen ◽

Jens Ole Eriksen ◽

Lise M. Lindahl ◽

Ulrike Wehkamp ◽

Gitte Rinds Andersen ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Protein Expression ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Early Stage ◽

Tumor Stage ◽

Skin Biopsies

Introduction Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and represents more than 50% of all primary cutaneous lymphomas. It is typically an indolent disorder with limited patches and plaques. One third, however, experience progression with ulcerating tumors and possible further systemic dissemination. Currently, the diagnosis of MF is based on clinical and histological examinations, but this has proven, especially in early-stage disease, to be challenging due to similarities with several benign skin conditions such as psoriasis, pityriasis lichenoides chronica, and dermatitis. Despite intensive research, reliable diagnostic biomarkers for early-stage MF are still needed. This study aims to identify a diagnostic classifier that could support the diagnostic workup leading to an exact diagnosis in the early-stage of this complex and potentially lethal disease. Methods We analyzed 43 formalin-fixed and paraffin-embedded (FFPE) skin biopsies from 36 patients with early-stage MF. Seven patients had 2 longitudinal biopsies available for analysis. These were compared with FFPE skin biopsies from patients with unspecified dermatitis (n=29) and healthy skin (n=12). All samples were collected from the archives of the Department of Pathology, Region Zealand, Denmark in the period 1990-2016. The histological samples were revised and clinical records were reviewed to establish the diagnosis and stage for each patient. Total RNA was extracted from ten 10-μm sections of FFPE tissue, and 50-100 ng of RNA was analyzed on the NanoString nCounter platform by applying the Myeloid Innate Immunity Panel, which quantifies the expression of 800 immune related genes. Differentially expressed genes (DEG, 2-fold change, p<0.05), were assessed by ANOVA, and a Support Vector Machine (SVM) diagnostic classifier was built based on 2-10 DEG and evaluated by 10-fold cross-validation. The classifier was tested on an independent, early-stage MF patient cohort (n=27). Protein expression was validated with immunohistochemistry and digitally analyzed by applying a specifically designed algorithm with the Leica Tissue IA 2.0 software. Double immunofluorescence staining protocols were developed to identify subtypes of TRAF1 positive cells in combination with various macrophage/dendritic cell markers (CD168, CD63, CD11c, CD1a, CD14, and S100) as well as T-cell (CD3) and B-cell (CD20) markers. Results A diagnostic classifier consisting of TOX and TRAF1 was able to distinguish early-stage MF from dermatitis with an overall accuracy of 85% in the discovery cohort and 80% in an independent validation cohort. TOX and TRAF1 protein levels were significantly elevated in early-stage MF compared to the dermatitis group (p < 0.0001). TOX and TRAF1 were also significantly increased in the progression from early-stage MF to tumor stage MF (p=0.003 and p=0.004, respectively). Subtypes of TRAF1-positive dendritic cells in early-stage MF consisted primarily of S100+ cells in both the epidermal and dermal compartment. A few TRAF1+ cells in the Pautrier microabscesses stained double positive with CD11c. In tumor stage MF the majority of TRAF1+ dendritic cells counterstained with CD1a and CD11c. Both neoplastic and reactive T-cells (CD3+) expressed TRAF1 in a minor degree in early-stage MF, while T-cells in tumor stage MF expressed TRAF1 in a much higher degree and the majority of the neoplastic T-cells were TRAF1 positive. No macrophages (CD68+ or CD163+) or B-cells double stained with TRAF1. Conclusion In the present study, we developed a two gene mRNA diagnostic classifier discriminating early-stage MF from dermatitis. The protein expression level of TOX and TRAF1 confirmed our gene expression levels and identified a highly significant difference between early-stage MF and dermatitis, which can prove useful in diagnostics of early-stage MF. Disclosures Andersen: Novo Nordisk: Other: Holds stock in Novo Nordisk; Hologic Deutchland GmbH: Research Funding. Odum:Micreos human Health B.V: Consultancy. Litman:Leo Pharma A/S: Research Funding. Gjerdrum:Nanostring Technologies: Other: Recieves founding from NanoString regarding a B-cell lymphoma research project., Research Funding; Celgene: Other: Celgene has funded the participation in ASH 2019.

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HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

Journal of Experimental Medicine ◽

10.1084/jem.20110278 ◽

2011 ◽

Vol 208 (7) ◽

pp. 1367-1376 ◽

Cited By ~ 904

Author(s):

Lewis Z. Shi ◽

Ruoning Wang ◽

Gonghua Huang ◽

Peter Vogel ◽

Geoffrey Neale ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Fate ◽

Treg Cell ◽

Cell Lineage ◽

Cellular Metabolism ◽

Treg Cells ◽

Glycolytic Pathway ◽

Metabolic Switch ◽

Glycolytic Activity

Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg cells) and controls cell fate determination. TH17 but not Treg cell–inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α–dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1α resulted in diminished TH17 development but enhanced Treg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.

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CD34+CD38dim cells in the human thymus can differentiate into T, natural killer, and dendritic cells but are distinct from pluripotent stem cells

Blood ◽

10.1182/blood.v87.12.5196.bloodjournal87125196 ◽

1996 ◽

Vol 87 (12) ◽

pp. 5196-5206 ◽

Cited By ~ 145

Author(s):

P Res ◽

E Martinez-Caceres ◽

A Cristina Jaleco ◽

F Staal ◽

E Noteboom ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Natural Killer ◽

Pluripotent Stem Cells ◽

Fetal Liver ◽

Cell Lineage ◽

Fetal Liver Cells

Recently we reported that the human thymus contains a minute population of CD34+CD38dim cells that do not express the T-cell lineage markers CD2 and CD5. The phenotype of this population resembled that of CD34+CD38dim cells present in fetal liver, umbilical cord blood, and bone marrow known to be highly enriched for pluripotent hematopoietic stem cells. In this report we tested the hypothesis that the CD34+CD38dim thymocytes constitute the most primitive hematopoietic cells in the thymus using a combination of phenotypic and functional analyses. It was found that in contrast to CD34+CD38dim cells from fetal liver and bone marrow, CD34+CD38dim cells from the thymus express high levels of CD45RA and are negative for Thy-1. These data indicate that the CD34+CD38dim thymocytes are distinct from pluripotent stem cells. CD34+CD38dim thymocytes differentiate into T cells when cocultured with mouse fetal thymic organs. In addition, individual cells in this population can differentiate either to natural killer cells in the presence of stem cell factor (SCF), interleukin-7 (IL-7), and IL-2 or to dendritic cells in the presence of SCF, granulocyte- macrophage colony-stimulating factor, and tumor necrosis factor alpha(TNFalpha), indicating that CD34+CD38dim thymocytes contain multi- potential hematopoietic progenitors. To establish which CD34+ fetal liver subpopulation contains the cells that migrate to the thymus, we investigated the T-cell-developing potential of CD34+CD38dim and CD34+CD38+ fetal liver cells and found that the capacity of CD34+ fetal liver cells to differentiate into T cells is restricted to those cells that are CD38dim. Collectively, these findings indicate that cells from the CD34+CD38dim fetal liver cell population migrate to the thymus before upregulating CD38 and ommitting to the T-cell lineage.

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Aberrant T cell differentiation in the absence of Dicer

Journal of Experimental Medicine ◽

10.1084/jem.20050678 ◽

2005 ◽

Vol 202 (2) ◽

pp. 261-269 ◽

Cited By ~ 444

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.

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Distinct Roles for Signals Relayed through the Common Cytokine Receptor γ Chain and Interleukin 7 Receptor α Chain in Natural T Cell Development

Journal of Experimental Medicine ◽

10.1084/jem.186.2.331 ◽

1997 ◽

Vol 186 (2) ◽

pp. 331-336 ◽

Cited By ~ 40

Author(s):

Alina Boesteanu ◽

A. Dharshan De Silva ◽

Hiroshi Nakajima ◽

Warren J. Leonard ◽

Jacques J. Peschon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lineage ◽

Absolute Number ◽

Cell Number ◽

Cytokine Receptor ◽

Interleukin 7 ◽

Deficient Mice ◽

Cell Ontogeny

The commitment, differentiation, and expansion of mainstream α/β T cells during ontogeny depend on the highly controlled interplay of signals relayed by cytokines through their receptors on progenitor cells. The role of cytokines in the development of natural killer (NK)1+ natural T cells is less clearly understood. In an approach to define the role of cytokines in the commitment, differentiation, and expansion of NK1+ T cells, their development was studied in common cytokine receptor γ chain (γc) and interleukin (IL)-7 receptor α (IL-7Rα)–deficient mice. These mutations block mainstream α/β T cell ontogeny at an early prethymocyte stage. Natural T cells do not develop in γc-deficient mice; they are absent in the thymus and peripheral lymphoid organs such as the liver and the spleen. In contrast, NK1+ T cells develop in IL-7Rα–deficient mice in the thymus, and they are present in the liver and in the spleen. However, the absolute number of NK1+ T cells in the thymus of IL-7Rα–deficient mice is reduced to ∼10%, compared to natural T cell number in the wild-type thymus. Additional data revealed that NK1+ T cell ontogeny is not impaired in IL-2– or IL-4–deficient mice, suggesting that neither IL-2, IL-4, nor IL-7 are required for their development. From these data, we conclude that commitment and/or differentiation to the NK1+ natural T cell lineage requires signal transduction through the γc, and once committed, their expansion requires signals relayed through the IL-7Rα.

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