HTLV-1 Dysregulates IL-6 and IL-10-JAK/STAT Signaling and Induces Leukemia/Lymphoma of Mature CD4+ T Cells with Regulatory T-Cell-like Signatures

Human T-cell leukemia virus, type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and chronic inflammatory diseases (e.g., HTLV-1 associated myelopathy, uveitis). Among viral genes encoded in the HTLV-1 provirus, HTLV-1 bZIP factor (HBZ) is the most important gene for its pathogenesis, since HBZ is constantly expressed in all ATL cases, and has a potential to enhance T-cell proliferation. We generated HBZ transgenic (Tg) mice and found that almost all mice developed systemic inflammation, such as dermatitis, and about 40% of mice suffered from T-cell lymphoma. In addition, this mouse demonstrates the similar immunophenotypes to HTLV-1-infected subjects, such as increase of effector/memory and Foxp3-expressing regulatory T cells (Tregs), indicating that it is a good animal model to analyze the molecular mechanisms of pathogenesis by HTLV-1. There is a clear correlation between the severity of inflammation and the incidence of T-cell lymphoma, suggesting that some immune factors are closely involved in oncogenesis by HBZ.

Recent studies showed that several pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6), participate in not only inflammation but also tumor development. Especially, IL-6 has been reported to play important roles in oncogenesis, tumor progression, angiogenesis and migration.

To clarify the roles of IL-6 in HBZ-mediated lymphomagenesis, we crossed HBZ-Tg mice with IL-6 knockout (KO) mice. Contrary to our hypothesis, inflammation was exacerbated, and incidence of T-cell lymphomas was markedly increased in HBZ-Tg/IL-6KO mice. In the pathological analysis of the lymphoma tissues, the percentage of Foxp3+ cells were much higher in HBZ-Tg/IL-6KO mice than in HBZ-Tg mice. Moreover, flow cytometric analysis also showed that CD4+Foxp3+ T cells were increased in spleens from HBZ-Tg/IL-6KO mice compared with HBZ-Tg mice or WT mice. Since IL-6 inhibits TGF-beta-induced Foxp3 expression and subsequently suppresses differentiation to Tregs, our results suggest that depletion of IL-6 induces aberrant differentiation of CD4+ T cells toward Treg-like cells in HBZ-Tg mice and accelerates lymphomagenesis of this subset. RNA-seq and flow cytometric analyses revealed that expression of IL-10 was significantly higher in CD4+ T cells of HBZ-Tg/IL-6KO than HBZ-Tg. Importantly, IL-10 accelerated the proliferation of CD4+ T cells of HBZ-Tg whereas it did not influence control T cells. We also found that HBZ interacted with both STAT1 and STAT3, which are critical transcription factors in IL-10-JAK/STAT signaling pathways, and enhanced their transcriptional activities. Foxp3-expressing T cells and IL-10 are known to be immune-suppressive, but these results indicate that increased Foxp3-expressing T cells and activation of IL-10-JAK/STAT signaling are associated with inflammation and lymphomagenesis by HBZ in vivo.

Our results suggest that IL-6 and IL-10 have suppressive and promoting effects on HBZ-induced pathogenesis, respectively. It has been reported that progression of HTLV-1-associated diseases was observed in several HTLV-1 carriers after administration of anti-IL-6R antibody, Tocilizumab. Inhibition of IL-6/IL-6R signaling and consequent activation of Foxp3/IL-10/JAK/STAT axis seem to be important for HTLV-1 pathogenesis.