Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice

Mizuha Kosugi-Kanaya; Mizuha Kosugi-Kanaya; Mizuha Kosugi-Kanaya; Satoshi Ueha; Satoshi Ueha; Jun Abe; Jun Abe; Shigeyuki Shichino; Shigeyuki Shichino; Francis H. W. Shand; Francis H. W. Shand; Teppei Morikawa; Makoto Kurachi; Yusuke Shono; Naoto Sudo; Naoto Sudo; Ai Yamashita; Ai Yamashita; Fumiko Suenaga; Fumiko Suenaga; Akihiro Yokoyama; Akihiro Yokoyama; Wang Yong; Wang Yong; Masahiro Imamura; Takanori Teshima; Kouji Matsushima; Kouji Matsushima

doi:10.3389/fimmu.2017.01842

Frontiers in Immunology (Dec 2017)

Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice

Mizuha Kosugi-Kanaya,
Mizuha Kosugi-Kanaya,
Mizuha Kosugi-Kanaya,
Satoshi Ueha,
Satoshi Ueha,
Jun Abe,
Jun Abe,
Shigeyuki Shichino,
Shigeyuki Shichino,
Francis H. W. Shand,
Francis H. W. Shand,
Teppei Morikawa,
Makoto Kurachi,
Yusuke Shono,
Naoto Sudo,
Naoto Sudo,
Ai Yamashita,
Ai Yamashita,
Fumiko Suenaga,
Fumiko Suenaga,
Akihiro Yokoyama,
Akihiro Yokoyama,
Wang Yong,
Wang Yong,
Masahiro Imamura,
Takanori Teshima,
Kouji Matsushima,
Kouji Matsushima

Affiliations

Mizuha Kosugi-Kanaya: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Mizuha Kosugi-Kanaya: CREST, Japan Science and Technology Agency, Tokyo, Japan
Mizuha Kosugi-Kanaya: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Satoshi Ueha: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Satoshi Ueha: CREST, Japan Science and Technology Agency, Tokyo, Japan
Jun Abe: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Jun Abe: CREST, Japan Science and Technology Agency, Tokyo, Japan
Shigeyuki Shichino: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Shigeyuki Shichino: CREST, Japan Science and Technology Agency, Tokyo, Japan
Francis H. W. Shand: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Francis H. W. Shand: CREST, Japan Science and Technology Agency, Tokyo, Japan
Teppei Morikawa: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Makoto Kurachi: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Yusuke Shono: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Naoto Sudo: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Naoto Sudo: CREST, Japan Science and Technology Agency, Tokyo, Japan
Ai Yamashita: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Ai Yamashita: CREST, Japan Science and Technology Agency, Tokyo, Japan
Fumiko Suenaga: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Fumiko Suenaga: CREST, Japan Science and Technology Agency, Tokyo, Japan
Akihiro Yokoyama: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Akihiro Yokoyama: CREST, Japan Science and Technology Agency, Tokyo, Japan
Wang Yong: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Wang Yong: CREST, Japan Science and Technology Agency, Tokyo, Japan
Masahiro Imamura: Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan
Takanori Teshima: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Kouji Matsushima: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Kouji Matsushima: CREST, Japan Science and Technology Agency, Tokyo, Japan

DOI: https://doi.org/10.3389/fimmu.2017.01842
Journal volume & issue: Vol. 8

Abstract

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Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (TG) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that TG predominate over hematopoietic stem cell-derived T cells generated de novo (THSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting TG, in particular CD8+ TG, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of TG in the reconstituted host. Selective depletion of TG in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of TG and resulted in a lethal TG-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting TG in cGVHD.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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