Ex-vivo anti-CD3 stimulation of splenocytes revealed no differences in the levels of Teff cytokines between stressed and nonstressed mice, and there were also no significant differences in the secretion of monocyte-derived cytokines such as IL-1, TNF-α, IL-6, and MCP-1. Notably however, stimulation of splenocytes derived from stressed mice Atezolizumab clinical trial in the presence of MP revealed a significant reduction in its immunosuppressive effects compared to splenocytes derived from nonstressed mice. This was reflected by the increased levels of proinflammatory cytokines secreted from cells of both the innate and adaptive immune
systems BI 6727 cost predisposing a bias toward Th1-Th17 polarization. In addition, when CORT signaling was blocked throughout the course of stress, EAE exacerbation was prevented.
We therefore suggest that prolonged exposure to stress in C57BL/6 female mice exhibiting a highly active HPA axis consequently induces desensitization to CORT stimuli, which otherwise shifts toward Th2 polarization as observed either following CORT administration or under various stress paradigms [11, 29, 50, 51]. Having observed the impact of CORT-resistance on the effector function of Th1 and Th17 cells, we sought to determine the effect of CVS on the Treg population, which plays a key role in the regulation of EAE. In general, our findings show that stress increases the frequency of CD4+CD25+ T cells. This has also been shown previously in humans [52] and in animal models [53]. Accordingly, Buspirone HCl some studies demonstrated that direct administration
of steroid analogues (such as dexamethasone) enhances the proportion of CD4+CD25+ T cells in lymphoid organs [54]. However, our results demonstrate that within the CD4+CD25+ T cells, stress decreases the fraction of Foxp3 Treg cells. In addition, the ratio between CD4+CD25+CD127− and CD4+CD25+CD127+ T cells was significantly lower in stressed as compared with nonstressed mice. Comparing the frequencies of CD25+CD127− and CD25+CD127+ T cells (within the CD4+ T cells) between stressed and nonstressed mice revealed that CD127+ effector T cells were those which increased in stressed mice, while the CD127− T-cell population did not change. Thus, our results point to a decreased Treg/Teff ratio (rather than modulation of Treg-cell frequency per se) in response to CVS, resulting from an increase in the Teff subset. Whether this transient decrease in the Treg-cell fraction promotes EAE exacerbation should be further investigated by means of their regulatory function following CVS.
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