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Clinical Trial
. 2011;6(9):e24345.
doi: 10.1371/journal.pone.0024345. Epub 2011 Sep 2.

Influence of short-term glucocorticoid therapy on regulatory T cells in vivo

Silviu Sbiera  1 , Thomas Dexneit, Sybille D Reichardt, Kai D Michel, Jens van den Brandt, Sebastian Schmull, Luitgard Kraus, Melanie Beyer, Robert Mlynski, Sebastian Wortmann, Bruno Allolio, Holger M Reichardt, Martin Fassnacht
Affiliations
Clinical Trial

Influence of short-term glucocorticoid therapy on regulatory T cells in vivo

Silviu Sbiera et al. PLoS One. 2011.

Abstract

Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids (GCs).

Objective: We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naïve mice.

Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) 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 T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers.

Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8±1.8×10(4) cells/ml vs. 33±11×10(4) in control mice) and spleen (dexamethasone: 2.8±1.9×10(5)/spleen vs. 95±22×10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) 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 T(reg) 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 T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0±1.5% vs 3.4±1.5%*; AITR(+): 0.6±0.4 vs 0.5±0.3%, CD127(low): 4.0±1.3 vs 5.0±3.0%* and CTLA4+: 13.8±11.5 vs 15.6±12.5%; * p<0.05).

Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Modulation of CD4+ T cells and Treg cells by GCs in mice.
Peripheral blood (A, C, E) and spleen (B, D, E) cells from C57BL/6 mice were analyzed by flow cytometry before, 3 days after IP treatment with different dosages of dexamethasone and 14 days after IP treatment with 100 mg/kg dexamethasone followed by oral taper. The absolute numbers of CD4+ T cells (A, B) and CD4+CD25highFOXP3+ Treg cells (C, D) were assessed and the relative frequency of Treg cells amongst all CD4+ T cells was calculated (E, F); *p<0.05, **p<0.01.
Figure 2
Figure 2. Effect of GC on the function of Treg cells in vitro.
Th cells (5×104 cells / well) were incubated with Treg cells at different ratios in the presence of irradiated APC (30 Gy, 105 cells / well) and Con A (2,5 µg / ml) for 48 hrs, either with dexamethasone (dex, 5 nM) or without it (con). Resting Th cells as well as Th and Treg cells stimulated with Con A served as controls. Proliferation was determined by 3H-TdR incorporation during an additional 16 hrs culture period (A), IL-2 levels were directly measured in the supernatants by ELISA (B). All values were normalized to stimulated Th cells treated with or without Dex, respectively. In both panels the combined data of three independent experiments are depicted.
Figure 3
Figure 3. Modulation of CD4+ T cells and Treg cells by GCs in humans.
Peripheral blood cells from acute hearing loss patients before and 14 days after prednisolone treatment were analyzed by flow cytometry and the absolute numbers (A, C, E, G, I) and the frequency (B, D, F, H, J) of CD4+ T cells (A, B) and Treg cells (CD4+CD25high and FOXP3+ (C, D), AITR+ (E, F), CD127low (G, H) or CTLA4+ (I, J)) were assessed; *p<0.05, ***p<0.001.
Figure 4
Figure 4. Flow cytometric analysis of Treg cells according to different markers.
Peripheral blood from one representative hearing-loss patient treated for 3 days (A, C, E, G) and 14 days (B, D, F, H) with glucocorticoid regimen was analyzed for the presence of regulatory T cells according to the following markers: CD4+ CD25high and FOXP3+ (A, B), AITR+ (C, D) CD127low (E, F) and CTLA4+ (G, H). Only CD4+ cells are depicted and the percentages indicate the relative frequency of Treg cells within this subpopulation.
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