Transactivation of the transforming growth factor beta 1 (TGF-beta 1) gene by human T lymphotropic virus type 1 tax: a potential mechanism for the increased production of TGF-beta 1 in adult T cell leukemia.

Human T-cell lymphotropic virus type I (HTLV-I) has been associated with an adult form of T-cell leukemia as well as tropical spastic paraparesis, a neurodegenerative disease. Adult T-cell leukemia patients express high levels of the type 1 isoform of transforming growth factor-beta (TGF-beta 1), which is mediated by the effects of the HTLV-I Tax transactivator protein on the TGF-beta 1 promoter. To understand further the regulation of TGF-beta 1 expression by Tax, we examined its expression in transgenic mice carrying the HTLV-I tax gene. We show that tumors from these mice and other tissues, such as submaxillary glands and skeletal muscle, which express high levels of tax mRNA selectively express high levels of TGF-beta 1 mRNA and protein. Moreover, TGF-beta 1 significantly stimulated the incorporation of tritiated thymidine into one of three cell lines derived from neurofibromas of tax-transgenic mice, which suggests that the excessive production of TGF-beta 1 may play a role in tumorigenesis and that these mice may serve as a useful model for studying the biological effects of TGF-beta in vivo.

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Overexpression of transforming growth factor-beta in transgenic mice carrying the human T-cell lymphotropic virus type I tax gene

Molecular and Cellular Biology ◽

10.1128/mcb.11.10.5222-5228.1991 ◽

1991 ◽

Vol 11 (10) ◽

pp. 5222-5228

Author(s):

S J Kim ◽

T S Winokur ◽

H D Lee ◽

D Danielpour ◽

K Y Kim ◽

...

Keyword(s):

T Cell ◽

Growth Factor ◽

Transgenic Mice ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Type I ◽

Tgf Beta ◽

Cell Leukemia ◽

Human T Cell ◽

Growth Factor Beta

Human T-cell lymphotropic virus type I (HTLV-I) has been associated with an adult form of T-cell leukemia as well as tropical spastic paraparesis, a neurodegenerative disease. Adult T-cell leukemia patients express high levels of the type 1 isoform of transforming growth factor-beta (TGF-beta 1), which is mediated by the effects of the HTLV-I Tax transactivator protein on the TGF-beta 1 promoter. To understand further the regulation of TGF-beta 1 expression by Tax, we examined its expression in transgenic mice carrying the HTLV-I tax gene. We show that tumors from these mice and other tissues, such as submaxillary glands and skeletal muscle, which express high levels of tax mRNA selectively express high levels of TGF-beta 1 mRNA and protein. Moreover, TGF-beta 1 significantly stimulated the incorporation of tritiated thymidine into one of three cell lines derived from neurofibromas of tax-transgenic mice, which suggests that the excessive production of TGF-beta 1 may play a role in tumorigenesis and that these mice may serve as a useful model for studying the biological effects of TGF-beta in vivo.

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Recombinant type 1 transforming growth factor beta precursor produced in Chinese hamster ovary cells is glycosylated and phosphorylated.

Molecular and Cellular Biology ◽

10.1128/mcb.8.5.2229 ◽

1988 ◽

Vol 8 (5) ◽

pp. 2229-2232 ◽

Cited By ~ 36

Author(s):

A M Brunner ◽

L E Gentry ◽

J A Cooper ◽

A F Purchio

Keyword(s):

Growth Factor ◽

Transforming Growth Factor Beta ◽

Chinese Hamster Ovary ◽

Transforming Growth Factor ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Tgf Beta ◽

Ovary Cells ◽

Growth Factor Beta

Analyses of cDNA clones coding for simian type 1 transforming growth factor beta (TGF-beta 1) suggest that there are three potential sites for N-linked glycosylation located in the amino terminus of the precursor region. Analysis of [3H]glucosamine-labeled serum-free supernatants from a line of Chinese hamster ovary cells which secrete high levels of recombinant TGF-beta 1 indicate that the TGF-beta 1 precursor, but not the mature form, is glycosylated. Digestion with neuraminidase resulted in a shift in migration of the two TGF-beta 1 precursor bands, which suggests that they contain sialic acid residues. Endoglycosidase H had no noticeable effect. Treatment with N-glycanase produced two faster-migrating sharp bands, the largest of which had a molecular weight of 39 kilodaltons. TGF-beta 1-specific transcripts produced by SP6 polymerase programmed the synthesis of a 42-kilodalton polypeptide which, we suggest, is the unmodified protein backbone of the precursor. Labeling with 32Pi showed that the TGF-beta 1 precursor was phosphorylated in the amino portion of the molecule.

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Transforming growth factor beta suppresses human immunodeficiency virus expression and replication in infected cells of the monocyte/macrophage lineage.

Journal of Experimental Medicine ◽

10.1084/jem.173.3.589 ◽

1991 ◽

Vol 173 (3) ◽

pp. 589-597 ◽

Cited By ~ 109

Author(s):

G Poli ◽

A L Kinter ◽

J S Justement ◽

P Bressler ◽

J H Kehrl ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Growth Factor ◽

Cell Line ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Tgf Beta ◽

Immunodeficiency Virus ◽

Growth Factor Beta

The pleiotropic immunoregulatory cytokine transforming growth factor beta (TGF-beta) potently suppresses production of the human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome, in the chronically infected promonocytic cell line U1. TGF-beta significantly (50-90%) inhibited HIV reverse transcriptase production and synthesis of viral proteins in U1 cells stimulated with phorbol myristate acetate (PMA) or interleukin 6 (IL-6). Furthermore, TGF-beta suppressed PMA induction of HIV transcription in U1 cells. In contrast, TGF-beta did not significantly affect the expression of HIV induced by tumor necrosis factor alpha (TNF-alpha). These suppressive effects were not mediated via the induction of interferon alpha (IFN-alpha). TGF-beta also suppressed HIV replication in primary monocyte-derived macrophages infected in vitro, both in the absence of exogenous cytokines and in IL-6-stimulated cultures. In contrast, no significant effects of TGF-beta were observed in either a chronically infected T cell line (ACH-2) or in primary T cell blasts infected in vitro. Therefore, TGF-beta may play a potentially important role as a negative regulator of HIV expression in infected monocytes or tissue macrophages in infected individuals.

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Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.

Journal of Experimental Medicine ◽

10.1084/jem.163.5.1037 ◽

1986 ◽

Vol 163 (5) ◽

pp. 1037-1050 ◽

Cited By ~ 1062

Author(s):

J H Kehrl ◽

L M Wakefield ◽

A B Roberts ◽

S Jakowlew ◽

M Alvarez-Mon ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Transforming Growth Factor Beta ◽

Potential Role ◽

Transforming Growth Factor ◽

Cell Types ◽

Tgf Beta ◽

Activated T Cells ◽

Growth Factor Beta

This study examines the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposes that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. TGF-beta was shown to inhibit IL-2-dependent T cell proliferation. The addition of picograms amounts of TGF-beta to cultures of IL-2-stimulated human T lymphocytes suppressed DNA synthesis by 60-80%. A potential mechanism of this inhibition was found. TGF-beta inhibited IL-2-induced upregulation of the IL-2 and transferrin receptors. Specific high-affinity receptors for TGF-beta were found both on resting and activated T cells. Cellular activation was shown to result in a five- to sixfold increase in the number of TGF-beta receptors on a per cell basis, without a change in the affinity of the receptor. Finally, the observations that activated T cells produce TGF-beta mRNA and that TGF-beta biologic activity is present in supernatants conditioned by activated T cells is strong evidence that T cells themselves are a source of TGF-beta. Resting T cells were found to have low to undetectable levels of TGF-beta mRNA, while PHA activation resulted in a rapid increase in TGF-beta mRNA levels (within 2 h). Both T4 and T8 lymphocytes were found to make mRNA for TGF-beta upon activation. Using both a soft agar assay and a competitive binding assay, TGF-beta biologic activity was found in supernatants conditioned by T cells; T cell activation resulted in a 10-50-fold increase in TGF-beta production. Thus, TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta.

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Case Report: HTLV-1–Induced Adult T-Cell Leukemia and Tropical Spastic Paresis

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.20-1656 ◽

2021 ◽

Author(s):

Reece Rosenthal ◽

Julika Kaplan ◽

Mohammed Ahmed ◽

Martha Mims ◽

Jill E. Weatherhead

Keyword(s):

T Cell ◽

Lower Extremity ◽

Spastic Paraparesis ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Lower Extremity Weakness ◽

T Lymphotropic Virus ◽

Adult T Cell Leukemia ◽

Spastic Paresis

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus endemic in many areas around the world. HTLV-1 can induce the development of adult T-cell leukemia (ATL) or myelopathy/tropical spastic paraparesis (HAM/TSP). We report a patient who presented to our outpatient clinic with massive splenomegaly, weight loss, urinary retention, and lower extremity weakness for the previous 3 years. The patient was found to have positive HTLV-1 by ELISA and Western blot from peripheral blood. Evaluation of the spleen demonstrated T-cell large granular lymphocyte leukemia consistent with ATL. In addition to progressive lower extremity weakness, hyperreflexia and clonus, cerebral spinal fluid was positive for HTLV-1 by ELISA and had a reversed CD4-to-CD8 ratio consistent with HAM/TSP. These findings suggest HTLV-1 induced ATL and HAM/TSP presenting simultaneously in the same patient.

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Preliminary study on immunotherapy for adult T-cell leukemia — induction of human T lymphotropic virus type 1-specific cytotoxic T lymphocytes

Journal of Dermatological Science ◽

10.1016/0923-1811(93)91095-c ◽

1993 ◽

Vol 6 (1) ◽

pp. 66

Author(s):

Yoshihiko Katahira ◽

Mitsuru Setoyama ◽

Tamotsu Kanzaki ◽

Shunro Sonoda

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Virus Type ◽

T Cell Leukemia ◽

Cell Leukemia ◽

T Lymphotropic Virus ◽

Adult T Cell Leukemia ◽

Preliminary Study

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Possible origin of adult T-cell leukemia/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells

Cancer Science ◽

10.1111/j.1349-7006.2005.00080.x ◽

2005 ◽

Vol 96 (8) ◽

pp. 527-533 ◽

Cited By ~ 82

Author(s):

Tomoko Kohno ◽

Yasuaki Yamada ◽

Norihiko Akamatsu ◽

Simeru Kamihira ◽

Yoshitaka Imaizumi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Virus Type ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Lymphoma Cells ◽

T Lymphotropic Virus ◽

Adult T Cell Leukemia

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Elevation of Memory Cytotoxic T Lymphocytes, Including Human T Lymphotropic Virus Type 1 Tax-Specific and Hepatitis Virus Type C-Specific Cytotoxic T Lymphocytes, in a Patient with Adult T-Cell Leukemia/Lymphoma and Hepatocellular Carcinoma

Case Reports in Oncology ◽

10.1159/000508092 ◽

2020 ◽

Vol 13 (2) ◽

pp. 802-806

Author(s):

Tatsuro Jo ◽

Yohei Kaneko ◽

Takayuki Oishi ◽

Kaori Matsuzaka ◽

Haruna Shioya ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Virus Type ◽

Hepatitis Virus ◽

Cell Leukemia ◽

T Lymphotropic Virus ◽

Adult T Cell Leukemia ◽

Type C

Herein, we present the case of a patient who suffered from adult T-cell leukemia/lymphoma (ATLL) and hepatocellular carcinoma (HCC) after obtaining a sustained virological response following treatment with a direct-acting antiviral (DAA) at different points in time. The patient went into complete remission (CR) for ATLL. Unfortunately, subsequent relapse of ATLL was observed. This situation was overcome using chemotherapy with pegylated interferon alpha-2b. Human T lymphotropic virus type 1 Tax-specific cytotoxic T lymphocytes (CTLs) were recognized after obtaining second CR, and those CTLs have been maintained for many years. After 4 years from the second CR, chronic hepatitis type C was treated with a DAA, and sustained virological response was attained. However, the occurrence of HCC was detected. Surprisingly, the tumor disappeared spontaneously. Hepatitis virus type C-specific CTLs were also detected in the patient. T-cell receptor (TCR) V beta gene repertoire analyses revealed oligoclonal expansion of effector and memory CTLs. The number of CTLs expressing the TCR V beta 13.1 has increased over the years since HCC occurrence. The activation and maintenance of anticancer cellular immunity may have allowed the patient to obtain long-term survival and overcome two lethal neoplasms.

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