Limits...
HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo.

Satou Y, Yasunaga J, Zhao T, Yoshida M, Miyazato P, Takai K, Shimizu K, Ohshima K, Green PL, Ohkura N, Yamaguchi T, Ono M, Sakaguchi S, Matsuoka M - PLoS Pathog. (2011)

Bottom Line: As a mechanism of increased T(reg) cells, HBZ expression directly induced Foxp3 gene transcription in T cells.HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of T(reg) cells.Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.

ABSTRACT
Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (T(reg)). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for T(reg) cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ T(reg) cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased T(reg) cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ T(reg) cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of T(reg) cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.

Show MeSH

Related in: MedlinePlus

HBZ-Tg mice develop T-cell lymphoma after a long latent period.(A) BrdU was injected into mice twice a day for three days, and splenocytes were stained with antibodies to BrdU, CD4, CD8, and B220. (B) Incidence of T-cell lymphoma in HBZ-Tg mice was statistically significant compared with that in non-Tg mice (P<0.001 by the logrank test). (C) Pleomorphic lymphoma in the cervical lymph node in a representative HBZ-Tg mouse. Infiltrations of lymphoma cells into lung, bone marrow, spleen and liver are also shown. (D) Expression of CD3 and CD4 in lymphoma cells was shown by immunohistochemical staining. (E) Immunohistochemical staining for Foxp3 in primary lymphomas of HBZ-Tg mice.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3037353&req=5

ppat-1001274-g002: HBZ-Tg mice develop T-cell lymphoma after a long latent period.(A) BrdU was injected into mice twice a day for three days, and splenocytes were stained with antibodies to BrdU, CD4, CD8, and B220. (B) Incidence of T-cell lymphoma in HBZ-Tg mice was statistically significant compared with that in non-Tg mice (P<0.001 by the logrank test). (C) Pleomorphic lymphoma in the cervical lymph node in a representative HBZ-Tg mouse. Infiltrations of lymphoma cells into lung, bone marrow, spleen and liver are also shown. (D) Expression of CD3 and CD4 in lymphoma cells was shown by immunohistochemical staining. (E) Immunohistochemical staining for Foxp3 in primary lymphomas of HBZ-Tg mice.

Mentions: To study the growth-promoting activity of the HBZ gene, we assessed the proliferation of CD4+ T cells in HBZ-Tg mice by incorporation of bromodeoxyuridine (BrdU), and found that the proliferation was three fold-higher than in non-Tg mice, whereas the proliferation of CD8+ T cells or B cells was not altered (Figure 2A, Table S1A). Transgenic expression of HBZ enhances the in vivo proliferation of mouse T cells, as ectopic expression of HBZ enhances the proliferation of human T cells [13], [15]. It is known that HTLV-1 transforms CD4+ T cells after a long latent period in a fraction of asymptomatic carriers [7]. Analogous to the development of ATL in humans, 14 of 37 (37.8%) HBZ-Tg mice of all three-founder lines developed T-cell lymphomas after 16 months, in contrast with 2 of 27 non-Tg mice (7.4%) (P<0.001 by the logrank test) (Figure 2B). In some transgenic mice, lymphoma cells infiltrated various organs including the lung, bone marrow, spleen and liver (Figure 2C). All of the lymphomas in HBZ-Tg mice were CD3+ and CD4+ by immunohistochemical analyses when examined before the mice became moribund (Figure 2D). Lymphoma cells also expressed αβT cell receptors on their surfaces (Figure S3). Monoclonal proliferation of these lymphoma cells was shown by single strand conformation polymorphism in Vγ2-Jγ1 junction region of T cell receptor γchain gene (Figure S4). Notably, the primary lymphoma cells expressed Foxp3 at various intensities in the majority of cases (Figure 2E, Table 1), exhibiting a similar FoxP3 staining pattern to that in lymph nodes in human ATL cases (Figure S5). Thus, the T-cell lymphomas in HBZ-Tg mice phenotypically resemble ATL, suggesting that HBZ promotes proliferation of CD4+ T cells and predisposes expressing cells to transform in due course.


HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo.

Satou Y, Yasunaga J, Zhao T, Yoshida M, Miyazato P, Takai K, Shimizu K, Ohshima K, Green PL, Ohkura N, Yamaguchi T, Ono M, Sakaguchi S, Matsuoka M - PLoS Pathog. (2011)

HBZ-Tg mice develop T-cell lymphoma after a long latent period.(A) BrdU was injected into mice twice a day for three days, and splenocytes were stained with antibodies to BrdU, CD4, CD8, and B220. (B) Incidence of T-cell lymphoma in HBZ-Tg mice was statistically significant compared with that in non-Tg mice (P<0.001 by the logrank test). (C) Pleomorphic lymphoma in the cervical lymph node in a representative HBZ-Tg mouse. Infiltrations of lymphoma cells into lung, bone marrow, spleen and liver are also shown. (D) Expression of CD3 and CD4 in lymphoma cells was shown by immunohistochemical staining. (E) Immunohistochemical staining for Foxp3 in primary lymphomas of HBZ-Tg mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037353&req=5

ppat-1001274-g002: HBZ-Tg mice develop T-cell lymphoma after a long latent period.(A) BrdU was injected into mice twice a day for three days, and splenocytes were stained with antibodies to BrdU, CD4, CD8, and B220. (B) Incidence of T-cell lymphoma in HBZ-Tg mice was statistically significant compared with that in non-Tg mice (P<0.001 by the logrank test). (C) Pleomorphic lymphoma in the cervical lymph node in a representative HBZ-Tg mouse. Infiltrations of lymphoma cells into lung, bone marrow, spleen and liver are also shown. (D) Expression of CD3 and CD4 in lymphoma cells was shown by immunohistochemical staining. (E) Immunohistochemical staining for Foxp3 in primary lymphomas of HBZ-Tg mice.
Mentions: To study the growth-promoting activity of the HBZ gene, we assessed the proliferation of CD4+ T cells in HBZ-Tg mice by incorporation of bromodeoxyuridine (BrdU), and found that the proliferation was three fold-higher than in non-Tg mice, whereas the proliferation of CD8+ T cells or B cells was not altered (Figure 2A, Table S1A). Transgenic expression of HBZ enhances the in vivo proliferation of mouse T cells, as ectopic expression of HBZ enhances the proliferation of human T cells [13], [15]. It is known that HTLV-1 transforms CD4+ T cells after a long latent period in a fraction of asymptomatic carriers [7]. Analogous to the development of ATL in humans, 14 of 37 (37.8%) HBZ-Tg mice of all three-founder lines developed T-cell lymphomas after 16 months, in contrast with 2 of 27 non-Tg mice (7.4%) (P<0.001 by the logrank test) (Figure 2B). In some transgenic mice, lymphoma cells infiltrated various organs including the lung, bone marrow, spleen and liver (Figure 2C). All of the lymphomas in HBZ-Tg mice were CD3+ and CD4+ by immunohistochemical analyses when examined before the mice became moribund (Figure 2D). Lymphoma cells also expressed αβT cell receptors on their surfaces (Figure S3). Monoclonal proliferation of these lymphoma cells was shown by single strand conformation polymorphism in Vγ2-Jγ1 junction region of T cell receptor γchain gene (Figure S4). Notably, the primary lymphoma cells expressed Foxp3 at various intensities in the majority of cases (Figure 2E, Table 1), exhibiting a similar FoxP3 staining pattern to that in lymph nodes in human ATL cases (Figure S5). Thus, the T-cell lymphomas in HBZ-Tg mice phenotypically resemble ATL, suggesting that HBZ promotes proliferation of CD4+ T cells and predisposes expressing cells to transform in due course.

Bottom Line: As a mechanism of increased T(reg) cells, HBZ expression directly induced Foxp3 gene transcription in T cells.HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of T(reg) cells.Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.

ABSTRACT
Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (T(reg)). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for T(reg) cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ T(reg) cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased T(reg) cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ T(reg) cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of T(reg) cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.

Show MeSH
Related in: MedlinePlus