INDEPENDENT EXPRESSION OF HUMAN T CELL DIFFERENTIATION ANTIGENS AND E ROSETTE RECEPTOR ON PHYTOHEMAGGLUTININ-STIMULATED T LYMPHOCYTES

Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a T cell neoplasm and several inflammatory diseases. A viral gene, HTLV-1 bZIP factor (HBZ), induces pathogenic Foxp3-expressing T cells and triggers systemic inflammation and T cell lymphoma in transgenic mice, indicating its significance in HTLV-1–associated diseases. Here we show that, unexpectedly, a proinflammatory cytokine, IL-6, counteracts HBZ-mediated pathogenesis. Loss of IL-6 accelerates inflammation and lymphomagenesis in HBZ transgenic mice. IL-6 innately inhibits regulatory T cell differentiation, suggesting that IL-6 functions as a suppressor against HBZ-associated complications. HBZ up-regulates expression of the immunosuppressive cytokine IL-10. IL-10 promotes T cell proliferation only in the presence of HBZ. As a mechanism of growth promotion by IL-10, HBZ interacts with STAT1 and STAT3 and modulates the IL-10/JAK/STAT signaling pathway. These findings suggest that HTLV-1 promotes the proliferation of infected T cells by hijacking the machinery of regulatory T cell differentiation. IL-10 induced by HBZ likely suppresses the host immune response and concurrently promotes the proliferation of HTLV-1 infected T cells.

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Modulated expression of notch1 during thymocyte development

Blood ◽

10.1182/blood.v88.3.970.970 ◽

1996 ◽

Vol 88 (3) ◽

pp. 970-976 ◽

Cited By ~ 111

Author(s):

RP Hasserjian ◽

JC Aster ◽

F Davi ◽

DS Weinberg ◽

J Sklar

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Flow Cytometric Analysis ◽

T Cell Differentiation ◽

Thymocyte Development ◽

Cd8 Cells ◽

Flow Cytometric ◽

Human T Cell ◽

Weak Staining ◽

Notch Gene

Abstract The Notch gene family encodes transmembrane proteins that have been implicated in control of diverse cellular differentiation events in the fly, frog, and mouse. Mammalian Notch1 is expressed at high levels in thymus and is mutated in a subset of human T-cell acute lymphoblastic neoplasms, suggesting a role in T-cell differentiation. To investigate the patterns of expression of NOTCH1 protein in thymocytes of the developing and mature thymus, antibodies raised against NOTCH1 were used to perform immunohistochemical and flow cytometric analyses. Strong staining for NOTCH1 within the fetal murine thymus was observed as early as 13.5 days postcoitum. By 17.5 days postcoitum, preferential staining of superficial cortical thymocytes was observed, with weak staining of developing medulla. Flow cytometric analysis and immunohistochemical staining of flow-sorted cells confirmed that the highest levels of NOTCH1 expression in adult murine thymus were present in immature cortical thymocytes (CD24high, CD4-CD8-). In contrast, NOTCH1 expression was low or absent in more mature cortical thymocytes (CD24low, CD4+CD8+), whereas intermediate levels of expression were observed in CD4+CD8- and CD4-CD8+ cells. These data indicate a dynamic pattern of NOTCH1 expression during T-cell differentiation and suggest that downregulation of NOTCH1 may be required for maturation of cortical thymocytes.

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Human T Cell Differentiation: New Techniques, Old Challenges

Bone Marrow Transplantation Across Major Genetic Barriers ◽

10.1142/9789814271271_0015 ◽

2010 ◽

pp. 351-371

Author(s):

Jean Plum ◽

Magda De Smedt ◽

Georges Leclercq ◽

Bart Vandekerckhove ◽

Tom Taghon

Keyword(s):

Cell Differentiation ◽

T Cell ◽

T Cell Differentiation ◽

New Techniques ◽

Human T Cell

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Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

Journal of Experimental Medicine ◽

10.1084/jem.20192360 ◽

2020 ◽

Vol 217 (9) ◽

Cited By ~ 1

Author(s):

Agata Cieslak ◽

Guillaume Charbonnier ◽

Melania Tesio ◽

Eve-Lyne Mathieu ◽

Mohamed Belhocine ◽

...

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Molecular Mechanisms ◽

Lymphoblastic Leukemia ◽

Ectopic Expression ◽

Regulatory Elements ◽

T Cell Differentiation ◽

Epigenetic Changes ◽

Human T Cell ◽

Cell Commitment

Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αβ T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.

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Enhanced differentiation of functional human T cells in NSGW41 mice with tissue-specific expression of human interleukin-7

10.1101/2020.04.24.060319 ◽

2020 ◽

Author(s):

Emilie Coppin ◽

Bala Sai Sundarasetty ◽

Susann Rahmig ◽

Jonas Blume ◽

Nikita A. Verheyden ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Regulatory Elements ◽

T Cell Differentiation ◽

Human Immune System ◽

Specific Expression ◽

Hematopoietic Stem ◽

Human T Cell ◽

Human T Cells

AbstractHumanized mouse models have become increasingly valuable tools to study human hematopoiesis and infectious diseases. However, human T cell differentiation remains inefficient. We generated mice expressing human interleukin (IL-7), a critical growth and survival factor for T cells, under the control of murine IL-7 regulatory elements. After transfer of human cord blood-derived hematopoietic stem and progenitor cells, transgenic mice on the NSGW41 background, termed NSGW41hIL7, showed elevated and prolonged human cellularity in the thymus while maintaining physiological ratios of thymocyte subsets. As a consequence, numbers of functional human T cells in the periphery were increased without evidence for pathological lymphoproliferation or aberrant expansion of effector or memory-like T cells. We conclude that the novel NSGW41hIL7 strain represents an optimized mouse model for humanization to better understand human T cell differentiation in vivo and to generate a human immune system with a better approximation of human lymphocyte ratios.

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In vitro T lymphopoiesis of human and rhesus CD34+ progenitor cells

Blood ◽

10.1182/blood.v87.10.4040.bloodjournal87104040 ◽

1996 ◽

Vol 87 (10) ◽

pp. 4040-4048 ◽

Cited By ~ 48

Author(s):

M Rosenzweig ◽

DF Marks ◽

H Zhu ◽

D Hempel ◽

KG Mansfield ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

T Lymphocytes ◽

Progenitor Cells ◽

T Cell Differentiation ◽

Hematopoietic Stem ◽

Human Cd34 ◽

Cd34 Cells

Differentiation of hematopoietic progenitor cells into T lymphocytes generally occurs in the unique environment of the thymus, a feature that has hindered efforts to model this process in the laboratory. We now report that thymic stromal cultures from rhesus macaques can support T-cell differentiation of human or rhesus CD34+ progenitor cells. Culture of rhesus or human CD34+ bone marrow-derived cells depleted of CD34+ lymphocytes on rhesus thymic stromal monolayers yielded CD3+CD4+CD8+, CD3+CD4+CD8-, and CD3+CD4-CD8+ cells after 10 to 14 days. In addition to classical T lymphocytes, a discrete population of CD3+CD8loCD16+CD56+ cells was detected after 14 days in cultures inoculated with rhesus CD34+ cells. CD3+ T cells arising from these cultures were not derived from contaminating T cells present in the CD34+ cells used to inoculate thymic stromal monolayers or from the thymic monolayers, as shown by labeling of cells with the lipophilic membrane dye PKH26. Expression of the recombinase activation gene RAG- 2, which is selectively expressed in developing lymphocytes, was detectable in thymic cultures inoculated with CD34+ cells but not in CD34+ cells before thymic culture or in thymic stromal monolayers alone. Reverse transcriptase-polymerase chain reaction analysis of T cells derived from thymic stromal cultures of rhesus and human CD34+ cells showed a polyclonal T-cell receptor repertoire. T-cell progeny derived from rhesus CD34+ cells cultured on thymic stroma supported vigorous simian immunodeficiency virus replication in the absence of exogenous mitogenic stimuli. Rhesus thymic stromal cultures provide a convenient means to analyze T-cell differentiation in vitro and may be useful as a model of hematopoietic stem cell therapy for diseases of T cells, including acquired immunodeficiency syndrome.

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