title: Glucocorticoids attenuate acute graft-versus-host disease by suppressing the cytotoxic capacity of CD8(+) T cells.
abstract: Glucocorticoids (GCs) are released from the adrenal gland during inflammation and help to keep immune responses at bay. Owing to their potent anti-inflammatory activity, GCs also play a key role in controlling acute graft-versus-host disease (aGvHD). Here we demonstrate that mice lacking the glucocorticoid receptor (GR) in T cells develop fulminant disease after allogeneic bone marrow transplantation. In a fully MHC-mismatched model, transfer of GR-deficient T cells resulted in severe aGvHD symptoms and strongly decreased survival times. Histopathological features were aggravated and infiltration of CD8(+) T cells into the jejunum was increased when the GR was not expressed. Furthermore, serum levels of IL-2, IFNγ, and IL-17 were elevated and the cytotoxicity of CD8(+) T cells was enhanced after transfer of GR-deficient T cells. Short-term treatment with dexamethasone reduced cytokine secretion but neither impacted disease severity nor the CTLs' cytolytic capacity. Importantly, in an aGvHD model in which disease development exclusively depends on the presence of CD8(+) T cells in the transplant, transfer of GR-deficient T cells aggravated clinical symptoms and reduced survival times as well. Taken together, our findings highlight that suppression of CD8(+) T-cell function is a crucial mechanism in the control of aGvHD by endogenous GCs.
authors.affiliation: Institute for Cellular and Molecular Immunology, University of Göttingen Medical School, Göttingen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Theiss-Suennemann
authors.forename: Katharina
authors.initials: K
authors.lastname: Jörß
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Messmann
authors.forename: Sybille D
authors.initials: SD
authors.lastname: Reichardt
authors.forename: Elena
authors.initials: E
authors.lastname: Montes-Cobos
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.forename: Hendrik
authors.initials: H
authors.lastname: AWolff
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Gudrun
authors.initials: G
authors.lastname: Strauß
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000494:pharmacology*; D006086:Graft vs Host Disease / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D007583:Jejunum / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D007376:Interleukin-2; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D007371:Interferon-gamma
keywords: CTL; GvHD; T cells; cytokines; glucocorticoids; inflammation; mice