HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and other inflammatory diseases in infected individuals. However, a complete understanding of how HTLV-1 transforms T cells is lacking. Expression of the chemokine receptor CCR4 on ATL cells and HTLV-1-infected cells suggested the hypothesis that CCR4 may mediate features of ATL and inflammatory diseases caused by HTLV-1. In this study, we show that the constitutively expressed HTLV-1 bZIP factor (HBZ) encoded by HTLV-1 is responsible for inducing CCR4 and its ability to promote T-cell proliferation and migration. Ectopic expression of HBZ was sufficient to stimulate expression of CCR4 in human and mouse T cells. Conversely, HBZ silencing in ATL cell lines was sufficient to inhibit CCR4 expression. Mechanistic investigations showed that HBZ induced GATA3 expression in CD4(+) T cells, thereby activating transcription from the CCR4 promoter. In an established air pouch model of ATL, we observed that CD4(+) T cells of HBZ transgenic mice (HBZ-Tg mice) migrated preferentially to the pouch, as compared with those in nontransgenic mice. Migration of CD4(+) T cells in HBZ-Tg mice was inhibited by treatment with a CCR4 antagonist. Proliferating (Ki67(+)) CD4(+) T cells were found to express high levels of CCR4 and CD103. Further, CD4(+) T-cell proliferation in HBZ-Tg mice was enhanced by coordinate treatment with the CCR4 ligands CCL17 and 22 and with the CD103 ligand E-cadherin. Consistent with this finding, we found that ATL cells in clinical skin lesions were frequently positive for CCR4, CD103, and Ki67. Taken together, our results show how HBZ activates CCR4 expression on T cells to augment their migration and proliferation, two phenomena linked to HTLV-1 pathogenesis. Cancer Res; 76(17); 5068-79. ©2016 AACR.

HTLV-1 bZIP Factor Enhances T-Cell Proliferation by Impeding the Suppressive Signaling of Co-inhibitory Receptors

“…Several mechanisms were identified for proliferation induced by HBZ [20, 26–31]. However, it remains unknown how HTLV-1 induces T-cell specific proliferation.…”

HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation

“…Authors suggested that CCL22 could be a major factor of target cell attraction, as infected cells express CCR4. However, a recent study demonstrated that CCR4 expression can be induced on infection and HBZ expression, hence it may not be initially expressed on target cells46. In contrast, BLT-1, the high-affinity LTB4 receptor, is expressed in a variety of inflammatory and immune cells, including macrophages, activated CD4 T cells, effector CD8 T cells and dendritic cells27.…”

The sense behind retroviral anti-sense transcription

“…This cell-type specific expression of HBZ has been shown to play a variety of roles in the pathogenesis of HTLV-mediated T-cell leukemia (reviewed in [3, 26]). For instance, HBZ transforms T-cells into a cancerous phenotype, in part by enhancing the expression of chemokine receptor CCR4 in this cell type, which promotes T-cell proliferation and migration [27]. HBZ also inhibits HTLV-1 sense transcription by recruiting essential transcription factors, such as CREB, away from the proviral sense promoter – this process facilitates HTLV-1 latency in infected T cells [3].…”