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Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma.

Kelly JA, Spolski R, Kovanen PE, Suzuki T, Bollenbacher J, Pise-Masison CA, Radonovich MF, Lee S, Jenkins NA, Copeland NG, Morse HC, Leonard WJ - J. Exp. Med. (2003)

Bottom Line: Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors.The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes.These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Heart and Blood Institute, National Cancer Institute, Bethesda, MD 20892-1674, USA.

ABSTRACT
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

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Effect of the Stat5b and TCR transgenes on CD4/CD8 flow cytometric profiles, activation state, and proliferative potential of thymocytes. (A) CD4/CD8 profiles for wild type vs. Stat5b transgenic thymocytes. CD4+/CD8+ (DP) thymocytes (day 0) were cultured with PMA + ionomycin for 24 h (day 1) followed by 48 h in RPMI (day 3 cells; reference 19). Similar results were obtained if anti-TCRβ (H57–597) + anti-CD2 (RM2–5) was used instead of PMA + ionomycin. (B) CD44/IL-2Rα profiles (gated on total population) for the same cells as in A. (C) Stat5b transgenic thymocytes exhibit augmented proliferation to IL-7, to anti-CD3 + anti-CD28, or to both stimuli.
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fig5: Effect of the Stat5b and TCR transgenes on CD4/CD8 flow cytometric profiles, activation state, and proliferative potential of thymocytes. (A) CD4/CD8 profiles for wild type vs. Stat5b transgenic thymocytes. CD4+/CD8+ (DP) thymocytes (day 0) were cultured with PMA + ionomycin for 24 h (day 1) followed by 48 h in RPMI (day 3 cells; reference 19). Similar results were obtained if anti-TCRβ (H57–597) + anti-CD2 (RM2–5) was used instead of PMA + ionomycin. (B) CD44/IL-2Rα profiles (gated on total population) for the same cells as in A. (C) Stat5b transgenic thymocytes exhibit augmented proliferation to IL-7, to anti-CD3 + anti-CD28, or to both stimuli.

Mentions: Because of the thymic origin of the lymphoma, we further evaluated thymocytes from WT and Stat5b transgenic mice in which lymphomas had not yet developed. After stimulation with PMA plus ionomycin (PI; Fig. 5 A), or anti-TCRβ plus anti-CD2 (unpublished data), both WT and Stat5b transgenic thymocytes had an increase in the percentage of CD8+ single positive T cells by day 1 (Fig. 5 A, panel c versus a and d versus b), and this increase was preferentially sustained in Stat5b transgenic mice until at least day 3 (Fig. 5 A, panel f versus e). The percentage of CD4+ cells was also increased in response to PI, but little if any difference was seen between WT and Stat5b transgenic mice (Fig. 5 A, panels d versus c and f versus e). The thymocyte differentiation/activation markers CD44 and IL-2Rα (CD25; reference 31) were more highly expressed on thymocytes from Stat5b transgenic mice as compared with WT mice (Fig. 5 B, panels d versus c and f versus e), and these Stat5b transgenic thymocytes proliferated more vigorously than wild type thymocytes in response to anti-CD3 plus anti-CD28, IL-7, or a combination of these stimuli (Fig. 5 C), or to stimulation with anti-TCRβ plus anti-CD2 (unpublished data). Thus, after various exogenous stimuli, Stat5b thymoctes, as compared with WT thymocytes, proliferated more vigorously and exhibited an increase in the number of CD8+ T cells and the percentage of these cells that were activated.


Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma.

Kelly JA, Spolski R, Kovanen PE, Suzuki T, Bollenbacher J, Pise-Masison CA, Radonovich MF, Lee S, Jenkins NA, Copeland NG, Morse HC, Leonard WJ - J. Exp. Med. (2003)

Effect of the Stat5b and TCR transgenes on CD4/CD8 flow cytometric profiles, activation state, and proliferative potential of thymocytes. (A) CD4/CD8 profiles for wild type vs. Stat5b transgenic thymocytes. CD4+/CD8+ (DP) thymocytes (day 0) were cultured with PMA + ionomycin for 24 h (day 1) followed by 48 h in RPMI (day 3 cells; reference 19). Similar results were obtained if anti-TCRβ (H57–597) + anti-CD2 (RM2–5) was used instead of PMA + ionomycin. (B) CD44/IL-2Rα profiles (gated on total population) for the same cells as in A. (C) Stat5b transgenic thymocytes exhibit augmented proliferation to IL-7, to anti-CD3 + anti-CD28, or to both stimuli.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196089&req=5

fig5: Effect of the Stat5b and TCR transgenes on CD4/CD8 flow cytometric profiles, activation state, and proliferative potential of thymocytes. (A) CD4/CD8 profiles for wild type vs. Stat5b transgenic thymocytes. CD4+/CD8+ (DP) thymocytes (day 0) were cultured with PMA + ionomycin for 24 h (day 1) followed by 48 h in RPMI (day 3 cells; reference 19). Similar results were obtained if anti-TCRβ (H57–597) + anti-CD2 (RM2–5) was used instead of PMA + ionomycin. (B) CD44/IL-2Rα profiles (gated on total population) for the same cells as in A. (C) Stat5b transgenic thymocytes exhibit augmented proliferation to IL-7, to anti-CD3 + anti-CD28, or to both stimuli.
Mentions: Because of the thymic origin of the lymphoma, we further evaluated thymocytes from WT and Stat5b transgenic mice in which lymphomas had not yet developed. After stimulation with PMA plus ionomycin (PI; Fig. 5 A), or anti-TCRβ plus anti-CD2 (unpublished data), both WT and Stat5b transgenic thymocytes had an increase in the percentage of CD8+ single positive T cells by day 1 (Fig. 5 A, panel c versus a and d versus b), and this increase was preferentially sustained in Stat5b transgenic mice until at least day 3 (Fig. 5 A, panel f versus e). The percentage of CD4+ cells was also increased in response to PI, but little if any difference was seen between WT and Stat5b transgenic mice (Fig. 5 A, panels d versus c and f versus e). The thymocyte differentiation/activation markers CD44 and IL-2Rα (CD25; reference 31) were more highly expressed on thymocytes from Stat5b transgenic mice as compared with WT mice (Fig. 5 B, panels d versus c and f versus e), and these Stat5b transgenic thymocytes proliferated more vigorously than wild type thymocytes in response to anti-CD3 plus anti-CD28, IL-7, or a combination of these stimuli (Fig. 5 C), or to stimulation with anti-TCRβ plus anti-CD2 (unpublished data). Thus, after various exogenous stimuli, Stat5b thymoctes, as compared with WT thymocytes, proliferated more vigorously and exhibited an increase in the number of CD8+ T cells and the percentage of these cells that were activated.

Bottom Line: Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors.The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes.These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Immunology, National Heart and Blood Institute, National Cancer Institute, Bethesda, MD 20892-1674, USA.

ABSTRACT
Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process.

Show MeSH
Related in: MedlinePlus