Modifying the classical suppression

Modifying the classical suppression PD-0332991 nmr assay to measure cytokine production by the responder (CD4+CD25–) T cells activated has revealed that there may be a hierarchy of suppression, with down-regulation of IFN-γ mRNA occurring earlier than suppression of Th2 cytokine production [79]. A similar study examining the transcriptional profile of T cells activated in the presence or absence of Tregs revealed down-regulation of factors promoting both Th1 and Th2 development [IL-12Rα, IL-12Rβ2 and Irf-4 as well as T-bet and GATA binding

protein 3 (GATA-3)] in ‘suppressed’ T cells [80]. Notably, expression of IL-21, a Th17-associated cytokine, was also suppressed upon co-culture, suggesting that Tregs can down-regulate at least one element of Th17 effector function. Sakaguchi

et al. reported that mice lacking CD25+ T cells develop exacerbated responses to non-self antigens and eventually develop various autoimmune selleck chemical pathologies [13]. This seminal observation implicated Tregs in governing the magnitude of immune responses and setting the threshold for the development of clinical autoimmune disease. If Tregs are particularly important in restraining one type of effector T cell response, this might be revealed by looking at what type of pathology is most prevalent in the absence of Tregs or when their regulatory function is impaired. aminophylline Several mouse models have been utilized to investigate defects in FoxP3 function with varied degrees of severity, from global impairment [18,81,82] and inducible ablation [34], to attenuated expression of FoxP3 [35], to Treg specific-disruption of selected suppressive mechanisms [30,31] or homing mechanisms [29]. T cells from scurfy mice are hyperproliferative to TCR ligation [17] and produce higher levels of cytokines than wild-type littermates [83]. Heightened production of IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IFN-γ and TNF-α in scurfy mice

indicated that components of both Th1 and Th2 responses are exacerbated in the absence of functional Tregs, while pathology results from an excessive ‘non-polarized’ response. Because IL-17 was not recognized as an important proinflammatory product of T cells at the time the scurfy mouse was characterized, levels of IL-17 were not determined. Mice with a targeted disruption of FoxP3 recapitulated the phenotype of scurfy mice displaying allergic airway inflammation and hyperproduction of immunoglobulin (Ig)E, indicative of overactive Th2 responses. However, both Th1 and Th2 cytokines were overproduced in FoxP3 knock-out mice, suggesting a non-selective dysregulation of both Th1 and Th2 responses [82].

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