Haruka Kinosada^1,2、Jun-ichirou Yasunaga¹、Kazuya Shimura¹、Paola Miyazato¹、Chiho Onishi¹、Tomonori Iyoda³、Kayo Inaba³、Masao Matsuoka^1,4

(1 Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, 2 Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, 3 Department of Animal Development and Physiology, Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, 4 Department of Hematology, Kumamoto University School of Medicine)

PLoS Pathogens (2017) doi.org/10.1371/journal.ppat.1006120

Human T-cell leukemia virus type 1 (HTLV-1) is the oncogenic retrovirus that causes adult T-cell leukemia (ATL). Since the receptor for HTLV-1 is glucose transporter 1, HTLV-1 infects not only T cells but also B cells and monocytes. However, most of the infected cells in vivo are CD4+ T cells. It remains unknown how HTLV-1 specifically promotes T-cell proliferation.
In this study, we revealed that HBZ targets various co-inhibitory receptors by two mechanisms, and enhances proliferation. One mechanism is downregulation of some co-inhibitory receptors, BTLA and LAIR-1. The other is functional suppression of some co-inhibitory receptors, TIGIT and PD-1.
These co-inhibitory receptors possess SHP-2 binding motifs, ITIM or ITSM. We found that HBZ interfered SHP-2 binding to these motifs and impaired the function of SHP-2 that deactivates TCR signaling. We also found that HBZ inhibits this binding by interacting with THEMIS, which forms a complex with Grb2 and SHP-2. In general, THEMIS is localized in the cytoplasm, whereas it has been reported that HBZ is localized in the nucleus. As previously reported, HBZ existed in the nucleus whereas THEMIS was localized in the cytoplasm when we express THEMIS or HBZ respectively. Interestingly, we found that THEMIS transfered the localization of HBZ from nucleus to cytoplasm when both proteins were co-expressed. Thus, HBZ functions in both nucleus and cytoplasm.
Since THEMIS is expressed only in T-lineage cells, our findings suggest that interaction between HBZ and THEMIS accounts for how HTLV-1 induces proliferation of only T cells in vivo.

This study is supported by the Project for Cancer Research And Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and development, AMED, and JSPS KAKENHI Grant, and a grant from Mitsubishi Foundation, and JSPS Core-to-Core Program A, Advanced Research Networks.