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Cd4+cd25+ regulatory t cell depletion modulates anxiety and depression-like behaviors in mice

PLoS ONE (2012) 7(7)
DOI: 10.1371/journal.pone.0042054
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Abstract

Stress has been shown to suppress immune function and increase susceptibility to inflammatory disease and psychiatric disease. CD4+CD25+ regulatory T (Treg) cells are prominent in immune regulation. This study was conducted to determine if anti-CD25 antibody (Ab) mediated depletion of Treg cells in mice susceptibility to stress-induced development of depression-like behaviors, as well as immunological and neurochemical activity. To accomplish this, an elevated plus-maze test (EPM), tail suspension test (TST), and forced swim test (FST) were used to examine depression-like behaviors upon chronic immobilization stress. Immune imbalance status was observed based on analysis of serum cytokines using a mouse cytometric bead array in conjunction with flow cytometry and changes in the levels of serotonin (5-HT) and dopamine (DA) in the brain were measured by high performance liquid chromatography (HPLC). The time spent in the open arms of the EPM decreased significantly and the immobility time in the FST increased significantly in the anti-CD25 Ab-treated group when compared with the non stressed wild-type group. In addition, interlukin-6 (IL-6), tumor necrosis factor-á (TNF-á), interlukin-2 (IL-2), interferon-gamma (IFN-γ), interlukin-4 (IL-4) and interlukin-17A (IL-17A) concentrations were significantly upregulated in the stressed anti-CD25 Ab-treated group when compared with the non stressed wild-type group. Furthermore, the non stressed anti-CD25 Ab-treated group displayed decreased 5-HT levels within the hippocampus when compared with the non stressed wild-type group. These results suggest that CD4+CD25+ Treg cell depletion modulated alterations in depressive behavior, cytokine and monoaminergic activity. Therefore, controlling CD4+CD25+ Treg cell function during stress may be a potent therapeutic strategy for the treatment of depression-like symptoms. © 2012 Kim et al.

Figures

  • Figure 1. Schedule of experimental procedures. Mice were divided into non-stressed WT mice, stressed WT mice, non-stressed CD4+CD25+ regulatory T (Treg) cells depleted mice, stressed CD4+CD25+ Treg cells depleted mice; from day 1 to 22, the stressed WT mice and stressed CD4+CD25+ Treg cells depleted mice received daily immobilization stress for 4 h and then were moved back to the home cage (three mice to a cage). An anti-CD25 antibody (Ab) was injected intraperitoneally once 24 h before CIS and then on the 8th day after the first CIS. On day 22, EPM, FST and TST were conducted in the afternoon (22 day) to determine depression and anxiety related behaviors after the previous day’s morning CIS. doi:10.1371/journal.pone.0042054.g001
  • Figure 2. Anti-CD25 Ab-induced depletion of CD4+CD25+ Treg cells in mice (n=8–10). Representative dot plots are shown for CD4+CD25+FOXP3+ cells. The efficacy of CD4+CD25+ Treg cell depletion was confirmed by flow cytometry analysis using PE-anti-mouse CD25 and fluorescent isothiocyanate- anti-mouse CD4 (A). Summaries of the percentage of positive cells are shown in (B) for CD4+CD25+FOXP3+ cells and are presented as the mean 6 SE. *** p,0.001 vs. the wild-type mice. doi:10.1371/journal.pone.0042054.g002
  • Figure 3. Effects of CD4+CD25+ Treg cells deficiency upon chronic immobilization stress in the elevated plus maze (n=14–16). After 21 days of stress, mice were individually placed in a central platform facing a closed arm and allowed to freely explore the maize for 5 min. Time spent in the open arms (A) and closed arms (B) of the maze and the frequency of entry into both arms (C) in the elevated plus maze. The time spent in the respective arms was recorded. Data were analyzed using separate one-way ANOVA followed by a post hoc Newman-Keuls test. ***p,0.001, *p,0.05 vs. the non-stressed control group. Vertical bars indicate the S.E. doi:10.1371/journal.pone.0042054.g003
  • Figure 4. Effects of CD4+CD25+ Treg cells deficiency on the durations of immobility in the forced swim test (n =14–16). After 21 days of stress, mice were individually placed in a glass cylinder (20 cm diameter625 cm high) containing water. During the 6 min test, the duration of immobility was observed and measured. The immobility time was regarded as the time spent by the mouse floating in the water without struggling. Data were analyzed using separate one-way ANOVA followed by a post hoc Newman-Keuls test. ** p,0.01 vs. the nonstressed control group. Vertical bars indicate the S.E. doi:10.1371/journal.pone.0042054.g004
  • Figure 5. Effects of CD4+CD25+ Treg cells deficiency on the durations of immobility in the tail suspension test (n=14–16). After 21 days of stress, mice were isolated in each chamber and suspended upside down by taping their tails to a flat metal bar so that they could not reach the top or the sides of the chamber. The mice were left in this position for 6 min and the total duration of immobility was measured. Data were analyzed using separate one-way ANOVA followed by a post hoc Newman-Keuls test. Vertical bars indicate the S.E. doi:10.1371/journal.pone.0042054.g005
  • Figure 6. Effects of CD4+CD25+ Treg cells deficiency on serum concentrations of the pro-inflammatory cytokines IL-6 (A), and TNF-á (B) (n =10–12). After the behavior tests, blood samples were collected from the mice by retro-orbital puncture. The serum prepared from each blood sample was then subjected to duplicate measurements for cytokine analysis using the mouse cytometric bead array (CBA). Data were analyzed using separate one-way ANOVA followed by a post hoc Newman-Keuls test. ** p,0.01, * p,0.05 vs. the stressed anti-CD25 Ab-treated group. Vertical bars indicate the S.E. doi:10.1371/journal.pone.0042054.g006
  • Figure 7. Effects of CD4+CD25+ Treg cells deficiency on serum concentrations of the Th1 cytokines IL-2 (A) and IFN-c (B) (n=10–12). After the behavior tests, blood samples were collected from the mice by retro-orbital puncture. The serum prepared from each blood sample was then subjected to duplicate measurements for cytokine analysis using the mouse cytometric bead array (CBA). Data were analyzed using separate one-way ANOVA followed by a post hoc Newman-Keuls test. ** p,0.01, * p,0.05 vs. the stressed anti-CD25 Ab-treated group. Vertical bars indicate the S.E. doi:10.1371/journal.pone.0042054.g007
  • Figure 8. Effects of CD4+CD25+ Treg cells deficiency on serum concentrations of the Th2 cytokine IL-4 (A) and the Th17 cytokine IL17A (B) (n =10–12). After the behavior tests, blood samples were collected from the mice by retro-orbital puncture. The serum prepared from each blood sample was subjected to duplicate measurements for cytokine analysis using the mouse cytometric bead array (CBA). Data were analyzed using separate one-way ANOVA followed by a post hoc Newman-Keuls test. *** p,0.00, ** p,0.01, * p,0.05 vs. the stressed anti-CD25 Ab-treated group. Vertical bars indicate the S.E. doi:10.1371/journal.pone.0042054.g008

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CITATION STYLE

APA

Kim, S. J., Lee, H., Lee, G., Oh, S. J., Shin, M. K., Shim, I., & Bae, H. (2012). Cd4+cd25+ regulatory t cell depletion modulates anxiety and depression-like behaviors in mice. PLoS ONE, 7(7). https://doi.org/10.1371/journal.pone.0042054

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