Glucocorticoids attenuate acute graft-versus-host disease by suppressing the cytotoxic capacity of CD8 super(+) T cells

• Published in: The Journal of pathology 2015-03, Vol.235 (4), p.646-655
• Main Authors: Theiss-Suennemann, Jennifer, Jors, Katharina, Messmann, Joanna J, Reichardt, Sybille D, Montes-Cobos, Elena, Luehder, Fred, Tuckermann, Jan P, AWolff, Hendrik, Dressel, Ralf, Grone, Hermann-Josef, Straus, Gudrun, Reichardt, Holger M
• Format: Article
• Language: English
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.4475

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 super(+) T cells into the jejunum was increased when the GR was not expressed. Furthermore, serum levels of IL-2, IFN gamma , and IL-17 were elevated and the cytotoxicity of CD8 super(+) 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 super(+) 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 super(+) T-cell function is a crucial mechanism in the control of aGvHD by endogenous GCs. Copyright copyright 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.