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

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

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01842

DOI=10.3389/fimmu.2017.01842

ISSN=1664-3224

ABSTRACT=<p>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 (T<sub>G</sub>) 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 T<sub>G</sub> predominate over hematopoietic stem cell-derived T cells generated <italic>de novo</italic> (T<sub>HSC</sub>) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting T<sub>G</sub>, in particular CD8<sup>+</sup> T<sub>G</sub>, 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 T<sub>G</sub> in the reconstituted host. Selective depletion of T<sub>G</sub> in the chronic phase of disease resulted in the expansion of T<sub>HSC</sub> and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, T<sub>HSC</sub> depletion caused activation of T<sub>G</sub> and resulted in a lethal T<sub>G</sub>-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting T<sub>G</sub> in cGVHD.</p>