Date Published: January 6, 2016
Publisher: Public Library of Science
Author(s): Keiko Yasuma, Jun-ichirou Yasunaga, Keiko Takemoto, Kenji Sugata, Yuichi Mitobe, Norihiro Takenouchi, Masanori Nakagawa, Yutaka Suzuki, Masao Matsuoka, Susan R Ross.
Human T-cell leukemia virus type 1 (HTLV-1) infects CD4+ T cells and induces proliferation of infected cells in vivo, which leads to the onset of adult T-cell leukemia (ATL) in some infected individuals. The HTLV-1 bZIP factor (HBZ) gene, which is encoded in the minus strand of HTLV-1, plays critical roles in pathogenesis. In this study, RNA-seq and ChIP-seq analyses using HBZ transduced T cells revealed that HBZ upregulates the expression and promoter acetylation levels of a co-inhibitory molecule, T cell immunoglobulin and ITIM domain (TIGIT), in addition to those of regulatory T cells related genes, Foxp3 and Ccr4. TIGIT was expressed on CD4+ T cells from HBZ-transgenic (HBZ-Tg) mice, and on ATL cells and HTLV-1 infected CD4+ T cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in vivo. Expression of Blimp1 and IL-10 was upregulated in TIGIT+CD4+ cells of HBZ-Tg mice compared with TIGIT-CD4+ T cells, suggesting the correlation between TIGIT expression and IL-10 production. When CD4+ T cells from HBZ-Tg mice were stimulated with TIGIT’s ligand, CD155, their production of the inhibitory cytokine IL-10 was enhanced. Furthermore, dendritic cells from HBZ-Tg mice produced high levels of IL-10 after stimulation. These data suggest that HBZ alters immune system to suppressive state via TIGIT and IL-10. Importantly, TIGIT suppressed T-cell responses to another HTLV-1 virus protein, Tax, in vitro. Blocking of TIGIT and PD-1 slightly increased anti-Tax T-cell activity in some HAM/TSP patients. These results suggest that HBZ-induced TIGIT on HTLV-1 infected cells impairs T-cell responses to viral antigens. This study shows that HBZ-induced TIGIT plays a pivotal role in attenuating host immune responses and shaping a microenvironment favorable to HTLV-1.
Oncogenic viruses, including Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), human papilloma virus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Merkel cell polyomavirus and human T-cell leukemia virus type 1 (HTLV-1), cause approximately 12% of human cancers. In these virus-induced cancers, a limited number of viral proteins play critical roles in oncogenesis—proteins that include HBx for HBV, E6 and E7 for HPV, and Tax and HTLV-1 bZIP factor (HBZ) for HTLV-1 . These viral proteins influence a cell’s epigenetic status and/or modulate a cell’s transcriptional machinery, leading to the transformation of infected cells.
Antigen recognition by the T-cell receptor and a second signal mediated by the CD28-CD80/86 co-stimulatory pathway are critical for T-cell activation. In addition, a multitude of other co-stimulatory and co-inhibitory pathways are also involved in T-cell activation . In particular, co-inhibitory receptors are pivotal in suppressing excess immune responses. Recently, antibodies to two co-inhibitory receptors, CTLA-4 and PD-1, called immune checkpoint blocking antibodies, have attracted attention as novel therapeutic drugs, since they exhibit remarkable clinical efficacy for patients with various cancers by reinvigorating exhausted CD8+ T cells . Here we demonstrate that the HBZ induces TIGIT expression, which leads to increased production of IL-10 via T cells and DCs. Increased IL-10 production is likely associated with immunosuppressive effects on the host immune system. Furthermore, this study suggests that TIGIT suppresses anti-Tax T-cell responses in vitro. Antibodies to TIGIT and/or PD-1 enhanced anti-Tax T-cell response in peripheral blood mononuclear cells (PBMCs) of HAM/TSP patients, which suggests that TIGIT and PD-1 are targets of treatment for HTLV-1 associated diseases.