Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 24, Pages 13740-13749Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1922884117
Keywords
HTLV-1; HBZ; IL-10; IL-6; JAK/STAT signaling pathway
Categories
Funding
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) [19cm0106611h0003, 19cm0106306h0004]
- Research Program on Emerging and Re-emerging Infectious Diseases from the Japan Agency for Medical Research and Development [18fk0108027h0003, 19fk0108088h0001]
- Japan Society for the Promotion of Science (JSPS) KAKENHI [19H03689, JP17K07166]
- Japan Leukemia Research Fund
- JSPS Core-to-Core Program A, Advanced Research Networks
- Japan Science and Technology Agency-Mirai Program [JPMJMI18G1]
- Grants-in-Aid for Scientific Research [19H03689] Funding Source: KAKEN
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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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