Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells In Vivo

Abstract

BackgroundPre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(Treg) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs).ObjectiveWe readdressed the influence of GC therapy on Treg cells in immunocompetent human subjects and naïve mice.MethodsMice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and Treg cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood Treg cells were analyzed prior and after a 14 day GC therapy based on different markers.ResultsRepeated GC administration to mice for three days dose-dependently decreased the absolute numbers of Treg cells in blood (100 mg dexamethasone/kg body weight: 2.8±1.8×104 cells/ml vs. 33±11×104 in control mice) and spleen (dexamethasone: 2.8±1.9×105/spleen vs. 95±22×105/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3+ Treg cells amongst the CD4+ T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of Treg cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating Treg cells in a relevant manner, although there was some variation depending on the definition of the Treg cells (FOXP3+: 4.0±1.5% vs 3.4±1.5%*; AITR+: 0.6±0.4 vs 0.5±0.3%, CD127low: 4.0±1.3 vs 5.0±3.0%* and CTLA4+: 13.8±11.5 vs 15.6±12.5%; * p<0.05).ConclusionShort-term GC therapy does not induce the hitherto supposed increase in circulating Treg cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating Treg cell numbers.

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

“…26 Consistent with these studies, the Dex-1, Dex-2, and Dex-Cont groups had significant reductions in circulating Treg cell levels from baseline (Figure 2D). Absolute Treg cell counts were also found to be lower in mice receiving combination anti-PD-1 and dexamethasone therapy, but these trends were not statistically significant.…”

“…The sensitivity of Treg cells to dexamethasone is controversial with multiple studies showing conflicting results. 26,32–36 Given this study’s findings, dexamethasone treatment could potentially have a positive influence on shaping antitumor immunity by reducing circulating Treg cell numbers and their subsequent tumor infiltration. 37 However, this potential positive influence must be counterbalanced with dexamethasone’s negative effects on conventional CD4+ and CD8+ T cells.…”

Increased Susceptibility to Allergic Asthma with the Impairment of Respiratory Tolerance Caused by Psychological Stress

“…Interestingly, the development of respiratory tolerance was prevented by systemic, but not local, GC administration [49], in accordance with our finding that the GC level in the circulation had increased. Systemic administration of GC to immunocompetent humans and naïve mice significantly reduced the number, but not the suppressive function, of Foxp3 + Treg cells in blood [50]. More importantly, either systemic or local GC administration during the sensitization and allergen-induced inflammation phases decreased the number of Foxp3 + Treg cells in mouse lungs [51].…”

Effets anti-inflammatoires et immunosuppresseurs des glucocorticoïdes

“…Cependant, ces données sont controversées et d'autres équipes ont trouvé, dans ce même modèle murin, que les lymphocytes T régulateurs sont supprimés après corticothérapie comme les autres populations T [29]. Par ailleurs, plusieurs études n'ont pas montré d'effet significatif des GCs sur les populations T régulatrices [30][31][32]. Une étude récente conduite chez des patients lupiques a certes mis en évidence une augmentation quantitative des lymphocytes T-Foxp3 après DXM, mais sans augmentation de leurs fonctions régulatrices [30].…”