GITR (glucocorticoid-induced TNFR family related gene) is a member of the TNFR superfamily (TNFRSF) that is expressed in different cell types, including T lymphocytes. Because of a high homology in its cytoplasmic region with other known costimulatory members of the TNFRSF, we investigated whether GITR played a costimulatory role in T lymphocyte subpopulations. Our results show that the proliferation response of CD8 + and CD4 + peripheral T cell subpopulations was potentiated when a GITR costimulus was added to an anti-CD3 stimulus. Furthermore, expression of the main activation-induced receptor (IL-2R § ) and production of IL-2 and IFN-+ were increased more with a GITR costimulus than with anti-CD3 alone. GITR stimulation also enhanced anti-CD3-induced ERK phosphorylation, suggesting that GITR is involved in MAPK-pathway activation. Interestingly, CD4 + CD25 + regulatory T cell (Treg cell) proliferation was triggered by the GITR costimulus; Treg cell proliferation was paralleled by the loss of the anergic phenotype and suppressor activity. Nevertheless, unstimulated GITR -/-CD4 + CD25 + and GITR +/+ CD4 + CD25 + cells were equally able to exert suppressor activity on CD4 + CD25 -responder cells. These results indicate a novel function for GITR as costimulatory molecule of T cell subsets.
By comparing untreated and dexamethasone-treated murine T cell hybridoma (3DO) cells by the differential display technique, we have cloned a new gene, GITR (glucocorticoid-induced tumor necrosis factor receptor family-related gene) encoding a new member of the tumor necrosis factor͞nerve growth factor receptor family. GITR is a 228-amino acids type I transmembrane protein characterized by three cysteine pseudorepeats in the extracellular domain and similar to CD27 and 4-1BB in the intracellular domain. GITR resulted to be expressed in normal T lymphocytes from thymus, spleen, and lymph nodes, although no expression was detected in other nonlymphoid tissues, including brain, kidney, and liver. Furthermore, GITR expression was induced in T lymphocytes upon activation by anti-CD3 mAb, Con A, or phorbol 12-myristate 13-acetate plus Caionophore treatment. The constitutive expression of a transfected GITR gene induced resistance to anti-CD3 mAbinduced apoptosis, whereas antisense GITR mRNA expression lead to increased sensitivity. The protection toward T cell receptor-induced apoptosis was specific, because other apoptotic signals (Fas triggering, dexamethasone treatment, or UV irradiation) were not modulated by GITR transfection. Thus, GITR is a new member of tumor necrosis factor͞nerve growth factor receptor family involved in the regulation of T cell receptor-mediated cell death.
Glucocorticoid-induced tumor necrosis factor receptor (GITR) on T cells and its natural ligand, GITRL, on accessory cells contribute to the control of immune homeostasis. Here we show that reverse signaling through GITRL after engagement by soluble GITR initiates the immunoregulatory pathway of tryptophan catabolism in mouse plasmacytoid dendritic cells, by means of noncanonical NF-kappaB-dependent induction of indoleamine 2,3-dioxygenase (IDO). The synthetic glucocorticoid dexamethasone administered in vivo activated IDO through the symmetric induction of GITR in CD4(+) T cells and GITRL in plasmacytoid dendritic cells. The drug exerted IDO-dependent protection in a model of allergic airway inflammation. Modulation of tryptophan catabolism via the GITR-GITRL coreceptor system might represent an effective therapeutic target in immune regulation. Induction of IDO could be an important mechanism underlying the anti-inflammatory action of corticosteroids.
Glucocorticoid‐induced TNFR‐related gene (GITR; TNFRSF18), a receptor belonging to the TNFR superfamily (TNFRSF), is activated by GITRL. GITR is expressed at low levels on resting responder T lymphocytes and is up‐regulated in T regulatory cells (Treg cells) and in activated T cells. GITRL is expressed in endothelial and antigen‐presenting cells. The cytoplasmic region of GITR has a striking homology with other TNFRSF members (4‐1BB, CD27, OX40) and binds TRAF molecules and Siva. Over recent years, the role of GITR in the development and in the pathophysiology of the immune system has been actively explored by several groups. GITR triggering induces both pro‐ and anti‐apoptotic effects, abrogates the suppressive activity of Treg cells and co‐stimulates responder T cells, with the latter activities over‐stimulating the immune system. In vivo, GITR activation causes development of autoimmune diseases and restores immune responses in a persistent retroviral infection model and in a tumor model. Intriguingly, GITR knockout mice demonstrate lower mortality in an ischemia model. The GITR‐GITRL system appears crucial in regulating immunity and warrants further study.
In this study, we describe the generation and characterization of mice in which GITR gene (TNFRSF18 [tumor
Glucocorticoids (GCs) are steroid hormones produced by the adrenal gland and regulated by the hypothalamus-pituitary-adrenal axis. GCs mediate effects that mostly result in transcriptional regulation of glucocorticoid receptor target genes. Mitogen-activated protein kinases (MAPKs) comprise a family of signaling proteins that convert extracellular stimuli into the activation of intracellular transduction pathways via phosphorylation of a cascade of substrates. They modulate a variety of physiological cell processes, such as proliferation, apoptosis, and development. However, when MAPKs are improperly activated by proinflammatory and/or extracellular stress stimuli, they contribute to the regulation of proinflammatory transcription factors, thus perpetuating activation of the inflammatory cascade. One of the mechanisms by which GCs exert their anti-inflammatory effects is negative interference with MAPK signaling pathways. Several functional interactions between GCs and MAPK signaling have been discovered and studied. Some of these interactions involve the GC-mediated up-regulation of proteins that in turn interfere with the activation of MAPK, such as glucocorticoid-induced-leucine zipper, MAPK phosphatase-1, and annexin-1. Other mechanisms include activated GR directly interacting with components of the MAPK pathway and negatively regulating their activation. The multiple interactions between GCs and MAPK pathways and their potential biological relevance in mediating the anti-inflammatory effects of GCs are reviewed.
Glucocorticoid-Induced TNFR-Related (GITR) protein belongs to Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and stimulates both the acquired and innate immunity. It is expressed in several cells and tissues, including T and Natural Killer (NK) cells and is activated by its ligand, GITRL, mainly expressed on Antigen Presenting Cells (APCs) and endothelial cells. GITR/GITRL system participates in the development of autoimmune/inflammatory responses and graft vs. host disease and potentiates response to infection and tumors. These effects are due to several concurrent mechanisms including: co-activation of effector T-cells, inhibition of regulatory T (Treg) cells, NK-cell co-activation, activation of macrophages, modulation of DC function and regulation of the extravasation process. In this chapter we describe: 1) the main structural features of GITR and GITRL, 2) the transduction pathways activated by GITR triggering, 3) the effects derived from GITR/GITRL system interaction, considering the interplay between the different cells of the immune system. Moreover, the potential use of GITR/GITRL modulators in disease treatment is discussed.
Glucocorticoid‐induced TNFR‐related protein (GITR) is a member of the TNFR superfamily, expressed in several cells and tissues including T lymphocytes, NK cells and antigen‐presenting cells (APC). GITR activation, upon interaction with its ligand (GITRL), functions as a co‐activating signal. GITRL is mainly expressed on APC and GITR/GITRL interaction is important for the development of immune response. This review summarizes recent results about the GITR/GITRL system, focusing on the interplay between APC, effector and regulatory T cells.
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