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.
Subject(s)
Bone Marrow Transplantation , Cytotoxicity, Immunologic/drug effects , Dexamethasone/pharmacology , Glucocorticoids/pharmacology , Graft vs Host Disease/prevention & control , Immunosuppressive Agents/pharmacology , Jejunum/drug effects , T-Lymphocytes, Cytotoxic/drug effects , Animals , Cells, Cultured , Disease Models, Animal , Graft vs Host Disease/blood , Graft vs Host Disease/genetics , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Interferon-gamma/blood , Interleukin-17/blood , Interleukin-2/blood , Jejunum/immunology , Jejunum/metabolism , Jejunum/pathology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Severity of Illness Index , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/transplantation , Time Factors , Transplantation, HomologousABSTRACT
Basal cell carcinoma (BCC) belongs to the group of non-melanoma skin tumors and is the most common tumor in the western world. BCC arises due to mutations in the tumor suppressor gene Patched1 (Ptch). Analysis of the conditional Ptch knockout mouse model for BCC reveals that macrophages and dendritic cells (DC) of the skin play an important role in BCC growth restraining processes. This is based on the observation that a clodronate-liposome mediated depletion of these cells in the tumor-bearing skin results in significant BCC enlargement. The depletion of these cells does not modulate Ki67 or K10 expression, but is accompanied by a decrease in collagen-producing cells in the tumor stroma. Together, the data suggest that cutaneous macrophages and DC in the tumor microenvironment exert an antitumor effect on BCC.
