Enhancement of anti-STLV-1/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody.

Kenji Sugata,Atae Utsunomiya,Michi Miura,Masanori Nakagawa,Michinori Kohara,Kisato Nosaka,Masao Matsuoka,Ki-Ryang Koh,Hitoshi Suzushima,Jun-Ichirou Yasunaga,Yuko Watanabe,Hirofumi Akari

doi:10.1038/srep27150

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia and inflammatory diseases. Because anti-HTLV-1 immune responses are critical for suppressing infected cells, enhancing cellular immunity is beneficial for the treatment of HTLV-1-associated diseases. Using simian T-cell leukemia virus type 1 (STLV-1) infected Japanese macaques, we analyzed the immune responses to viral antigens and the dynamics of virus-infected cells. The chemokine receptor CCR4 is expressed on STLV-1 infected cells, and administration of humanized monoclonal antibody to CCR4, mogamulizumab, dramatically decreased the number of STLV-1-infected cells in vivo. Concurrently, mogamulizumab treatment enhanced STLV-1 specific CD4+ and CD8+ T cell responses by simultaneously targeting CCR4+ effector regulatory T (Treg) cells and infected cells. Mogamulizumab promoted the phagocytosis of CCR4+ infected cells by macrophages, which likely enhanced antigen presentation. Vaccination with recombinant vaccinia virus (rVV) expressing viral antigens suppressed the proviral load and the number of Tax-expressing cells. Enhanced T-cell responses were also observed in some ATL patients who were treated with mogamulizumab. This study shows that mogamulizumab works not only by killing CCR4+ infected cells directly, but also by enhancing T cell responses by increasing the phagocytosis of infected cells by antigen-presenting cells and suppressing CCR4+ effector Treg cells.

Highlights

Human T-cell leukemia virus type 1 (HTLV-1) is transmitted mainly via cell-to-cell infection, and the infectivity of cell-free virus is very poor; in this respect it differs from another human retrovirus, human immunodeficiency virus type 1 (HIV-1)[1,2]
We have previously described simian T-cell leukemia virus type 1 (STLV-1) naturally infected Japanese macaques (Macaca fuscata) (JMs) as a model of HTLV-1 infection, and we reported that mogamulizumab strongly suppressed the number of STLV-1-infected cells in vivo[17]
Since it has been reported that Treg cells express chemokine receptor type 4 (CCR4) and suppress the protective immune responses to cancer and pathogens[15], we measured the number of Treg cells before and after mogamulizumab treatment

Summary

Introduction

Human T-cell leukemia virus type 1 (HTLV-1) is transmitted mainly via cell-to-cell infection, and the infectivity of cell-free virus is very poor; in this respect it differs from another human retrovirus, human immunodeficiency virus type 1 (HIV-1)[1,2]. The host immune response to this virus has a tremendous impact on the dynamics of the HTLV-1 infected cell population. We reported that CTLs to HBZ have protective effects against adult T-cell leukemia (ATL)[8]. ATL cells are CD4+CCR4+CADM1+, suggesting that HTLV-1 infects or increases this subpopulation of T cells and transforms them[13]. Humanized anti-CCR4 monoclonal antibody (mAb), mogamulizumab, has been developed for the treatment of ATL14. We found that mogamulizumab treatment induced a long-lasting decrease in the number of simian T-cell leukemia virus type 1 (STLV-1) infected cells in vivo by enhancing T-cell responses to viral antigens and suppressing Treg cells in vivo. Mogamulizumab elicits anti-HTLV-1 effects by killing CCR4+ T cells and enhancing T-cell responses to HTLV-1

Methods

Results

Conclusion