Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR, TNFRSF18, and CD357) is expressed at high levels in activated T cells and regulatory T cells (Tregs). In this review, we present data from mouse and human studies suggesting that GITR is a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs). The role of GITR in Treg expansion is confirmed by the association of GITR expression with markers of memory T cells. In this context, it is not surprising that GITR appears to be a marker of active Tregs, as suggested by the association of GITR expression with other markers of Treg activation or cytokines with suppressive activity (e.g., IL-10 and TGF-β), the presence of GITR⁺cells in tissues where Tregs are active (e.g., solid tumours), or functional studies on Tregs. Furthermore, some Treg subsets including Tr1 cells express either low or no classical Treg markers (e.g., FoxP3 and CD25) and do express GITR. Therefore, when evaluating changes in the number of Tregs in human diseases, GITR expression must be evaluated. Moreover, GITR should be considered as a marker for isolating Tregs.

Corticosteroids are the mainstay of therapy for many pediatric disorders and sometimes are life-saving. Both endogenous and synthetic derivatives diffuse across the cell membrane and, by binding to their cognate glucocorticoid receptor, modulate a variety of physiological functions, such as glucose metabolism, immune homeostasis, organ development, and the endocrine system. However, despite their proved and known efficacy, corticosteroids show a lot of side effects, among which growth retardation is of particular concern and specific for pediatric age. The aim of this review is to discuss the mechanism of action of corticosteroids, and how their genomic effects have both beneficial and adverse consequences. We will focus on the use of corticosteroids in different pediatric subspecialties and most common diseases, analyzing the most recent evidence.

Glucocorticoid‐induced TNFR‐related (gitr) is a gene coding for a member of the TNF receptor superfamily. GITR activation by its ligand (GITRL) influences the activity of effector and regulatory T cells, thus participating in the development of immune response against tumours and infectious agents, as well as in autoimmune and inflammatory diseases. Notably, treating animals with GITR‐Fc fusion protein ameliorates autoimmune/inflammatory diseases while GITR triggering, by treatment with anti‐GITR mAb, is effective in treating viral, bacterial and parasitic infections, as well in boosting immune response against tumours. GITR modulation has been indicated as one of the top 25 most promising research areas by the American National Cancer Institute, and a clinical trial testing the efficacy of an anti‐GITR mAb in melanoma patients has been started. In this review, we summarize results regarding: (i) the mechanisms by which GITRL/GITR system modulates immune response; (ii) the structural and functional studies clearly demonstrating differences between GITRL/GITR systems of mice and humans; (iii) the molecules with pharmacological activities including anti‐GITR mAbs, GITR‐Fc and GITRL‐Fc fusion proteins, GITRL in monomer or multimer conformation; and (iv) the possible risks deriving from GITRL/GITR system pharmacological modulation. In conclusion, GITR triggering and inhibition could be useful in treating tumours, infectious diseases, as well as autoimmune and inflammatory diseases. However, differences between mouse and human GITRL/GITR systems suggest that further preclinical studies are needed to better understand how safe therapeutic results can be obtained and to design appropriate clinical trials.

Treg subsets play a role in sustaining peripheral tolerance, are characterized by markers such as forkhead winged‐helix transcription factor (FOXP3) and CD25, and produce suppressive cytokines, such as IL‐10 and TGF‐β. Glucocorticoid‐induced TNF receptor family‐related (GITR) protein has been suggested to regulate Treg activity in mice. The aim of our study was to investigate GITR expression in human CD4⁺ T lymphocytes and its possible role in Treg function. Results indicate that a subset of CD4⁺ T cells in the peripheral blood expresses GITR and low levels of CD25 (CD4⁺CD25^lowGITR⁺). These cells show Treg features as they express FOXP3, IL‐10, TGF‐β and are anergic but, as opposed to natural Tregs, express low levels of CTLA‐4 and are CD127^high. CD4⁺CD25^lowGITR⁺ cells represent a low percentage of the CD4⁺ T‐cell population (0.32–1.74%) and are mostly memory cells. Functional experiments demonstrated that CD4⁺CD25^lowGITR⁺ cells have relevant suppressive activity that depends on TGF‐β. Moreover, an anti‐GITR Ab inhibited their suppressive activity, as observed in CD4⁺CD25⁺ murine Tregs. Taken together, these data indicate that human CD4⁺CD25^lowGITR⁺ cells represent a distinct Treg subpopulation.

Objective. CD4⁺CD25^lowGITR⁺ T lymphocytes expressing FoxP3 and showing regulatory function have been recently described in healthy donors (HD). The objective of the study was to investigate their presence and role in patients with primary SS (pSS). Methods. CD4⁺CD25^lowGITR⁺ cells circulating in peripheral blood (PB) of patients with pSS were isolated by MACS technique, their phenotype was studied by flow cytometry and real-time PCR, and their function was studied by in vitro co-culture. CD4⁺CD25^lowGITR⁺ cells infiltrating salivary glands (SGs) were revealed by immunohistochemistry. Results. Results indicated that conventional CD4⁺CD25^high regulatory T cells (Tregs) are decreased, whereas CD4⁺CD25^lowGITR⁺ cells are expanded in the PB of pSS as compared with HD. Phenotypic analysis demonstrated that CD4⁺CD25^lowGITR⁺ cells display Treg markers, including FoxP3, TGF-β and IL-10, and functional experiments demonstrated that they exert a strong inhibitory activity against autologous effector cells. CD4⁺CD25^lowGITR⁺ cells were detectable in great number in the SG inflammatory infiltrate. Interestingly, PB CD4⁺CD25^lowGITR⁺ cell expansion was evident only in patients with inactive disease, while conventional CD4⁺CD25^high Treg number was not associated with disease activity. Conclusion. The present data demonstrate that circulating CD4⁺ cells expressing GITR, but with low levels of CD25 (CD4⁺CD25^lowGITR⁺), are detectable in pSS patients. These cells, displaying Treg phenotype and function, are present in SG inflamed tissues and are expanded in the PB of subjects with inactive disease. Data suggest that the expansion of CD4⁺CD25^lowGITR⁺ cells in pSS may represent a counter-regulatory attempt against autoimmune-driven inflammation and may provide a new target for future treatment strategies.