title: Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+ and CD8+ T cells.
abstract: Prevention of chronic graft-versus-host disease (cGVHD) remains a major challenge in allogeneic hematopoietic cell transplantation (HCT) owing to limited understanding of cGVHD pathogenesis and lack of appropriate animal models. In this study, we report that, in classical acute GVHD models with C57BL/6 donors and MHC-mismatched BALB/c recipients and with C3H.SW donors and MHC-matched C57BL/6 recipients, GVHD recipients surviving for >60 d after HCT developed cGVHD characterized by cutaneous fibrosis, tissue damage in the salivary gland, and the presence of serum autoantibodies. Donor CD8(+) T cells were more potent than CD4(+) T cells for inducing cGVHD. The recipient thymus and de novo-generated, donor-derived CD4(+) T cells were required for induction of cGVHD by donor CD8(+) T cells but not by donor CD4(+) T cells. Donor CD8(+) T cells preferentially damaged recipient medullary thymic epithelial cells and impaired negative selection, resulting in production of autoreactive CD4(+) T cells that perpetuated damage to the thymus and augmented the development of cGVHD. Short-term anti-CD4 mAb treatment early after HCT enabled recovery from thymic damage and prevented cGVHD. These results demonstrate that donor CD8(+) T cells cause cGVHD solely through thymic-dependent mechanisms, whereas CD4(+) T cells can cause cGVHD through either thymic-dependent or independent mechanisms.
authors.affiliation: Department of Diabetes/Endocrinology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: James S
authors.initials: JS
authors.lastname: Young
authors.forename: Heather
authors.initials: H
authors.lastname: Johnston
authors.forename: Xiong
authors.initials: X
authors.lastname: Ni
authors.forename: Ruishu
authors.initials: R
authors.lastname: Deng
authors.forename: Jeremy
authors.initials: J
authors.lastname: Racine
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.forename: Audrey
authors.initials: A
authors.lastname: Wang
authors.forename: Ivan
authors.initials: I
authors.lastname: Todorov
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation*; D002908:Chronic Disease; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation