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.

The Role of Animal Models in the Study of Hematopoietic Stem Cell Transplantation and GvHD: A Historical Overview

“…Once T cells reach their target site, the tissue destruction occurs by direct induction of apoptosis mediated by TNF-α and IL-1 (112), and/or by killing mediated by cytotoxic CD8 + T cells through perforin/granzyme and Fas–FasL interactions. The suppression of CD8 + T cell function is crucial in the control of aGvHD (113). …”

GLCCI1 and Glucocorticoid Receptor Genetic Diversity and Response to Glucocorticoid-Based Treatment of Graft-versus-Host Disease

“…In a recent study by Theiss-Suennemann et al in a murine model, when recipients received allogeneic T cells lacking GR expression, aGVHD had a far more severe course than in controls [17]. This finding suggests an important role of donor T cells in the response to GC, although we have detected an effect on the determination of response in the genetic background of the recipient.…”

“…In the context of aGVHD, GC has further been found to suppress CD8-positive T cells [17]. Our understanding of GC resistance mainly derives from research conducted in the field of chronic inflammatory diseases and, in particular, asthma.…”

Effectiveness of palivizumab in children with childhood interstitial lung disease: The French experience

“…Corticosteroids have an immunosuppressive effect, with transient lymphopenia more pronounced for T cells and associated with a lower cytotoxic capacity of CD8 + T cells . As both the CD4 + and CD8 + lymphocyte subsets are involved in terminating RSV replication after primary infection, corticosteroids slow the decrease in the amount of RSV present in the lower respiratory tract .…”