Psoriatic Regulatory T cell Dysfunction

描述(由申请人提供)： 银屑病提供了一个独特的机会来剖析保护性调节性T细胞和致病的Th1和Th17型T细胞之间的相互作用。在银屑病中发现的Treg功能障碍与高IL-6水平以及这种细胞因子抑制调节性T细胞功能和刺激Th17分化的能力可能解释了观察到的银屑病T细胞反应的变化。根据我们的观察，a)在银屑病皮肤的关键T细胞微环境中产生高水平的IL-6，b)IL-6可以抑制人类T调节细胞对效应细胞增殖的抑制，以及c)银屑病T细胞表现出高反应性的STAT3磷酸化，测试IL-6和/或其他激活STAT3的细胞因子是否有助于TMEM/Jeff细胞逃避抑制是至关重要的。我们会这样做的。)确定银屑病皮损环境是否可以通过效应器T细胞对银屑病调节性T细胞的抑制产生屈光作用，从而造成银屑病Treg活性的功能性降低。在Treg方面，我们发表的和初步的数据表明，银屑病Treg的功能较差，在已发展的银屑病皮损中，数量不足以功能抑制，CCR5+Tregs的数量减少，对RANTES和Mip1a的趋化性降低，CD73减少，IFI27增加(ISG12)。此外，过度表达的银屑病STAT3相关信号细胞因子，如IL-6、IL-23和IL-22，与IL-1和TGFb相结合，可以将Tregs的前体细胞的分化从调节表型转移到致病的Th17细胞途径，甚至导致承诺的Tregs反式分化重新编程为产生IFNG、IL-17或TNF的TJeff细胞。因此，我们也将II。)确定银屑病皮损环境是否可以a)诱导银屑病Treg细胞的异常轮廓，b)将Treg细胞的分化从Treg向Th17‘S转移，或c)导致Treg细胞的反式分化重新编程为TJeff细胞。设计一种模型来概括在牛皮癣中观察到的效应/调节性T细胞的变化，将允许对潜在的治疗试剂进行高通量分析，并在调节性T细胞发挥作用的疾病中打开新的研究机会。 公共卫生相关性： 目前的应用建议剖析保护性调节性T细胞与致病性Th1和Th17型T细胞之间的相互作用。为了深入了解已经用于治疗牛皮癣、克隆氏症和类风湿/牛皮癣关节炎的药物的作用机制(S)，有必要更全面地了解银屑病中调节效应T细胞和致病效应T细胞之间的关系。更好地了解有效疗法的机制将有助于改进下一代疗法，并确定更多量身定做的干预目标。

DESCRIPTION (provided by applicant): Psoriasis presents a unique opportunity to dissect the interplay between protective regulatory T cells, and pathogenic Th1 and Th17 type T cells. Findings in psoriasis of Treg dysfunction in combination with high IL-6 levels and the capacity of this cytokine to inhibit regulatory T cell function and stimulate Th17 differentiation may explain observed alterations in psoriatic T cell response. Based upon our observations that a) IL-6 is produced at high levels in critical T cell microenvironments in psoriatic skin, b) that IL-6 can inhibit suppression of effector cell proliferation by human T regulatory cells, and c) that psoriatic T cells exhibit hyper-responsive phosphorylation of STAT3, it is critical to test whether IL-6 and and/or other STAT3-activating cytokines favor escape for Tmem/eff cells from suppression. Thus we will I.) Determine whether the psoriatic lesional milieu can create functionally decreased psoriatic Treg activity via effector T cells becoming refractive to suppression by psoriatic regulatory T cells. On the Treg side, our published and preliminary data demonstrate that psoriatic Tregs are functionally less effective, are insufficient numerically to functionally suppress in developed psoriatic lesions, have decreased numbers of CCR5+ Tregs, decreased chemotaxis to Rantes and Mip1a, decreased CD73, and increased IFI27 (ISG12). Furthermore, over-expressed psoriatic STAT3-associated signaling cytokines such as IL-6, IL-23, and IL-22, in combination with IL- 1 and TGFb, can divert the differentiation of Tregs from precursors away from a regulatory phenotype and toward a pathogenic Th17 cell pathway, or even cause trans-differentiative re-programming of committed Tregs into IFNg-, IL-17-,or TNF-producing Teff cells. Therefore, we will also II.) Determine whether the psoriatic lesional milieu can a) induce the abnormal profile of psoriatic Treg cells, b) divert differentiation away from Treg development toward Th17's, or c) cause trans-differentiative re-programming of Tregs into Teff cells. Designing a model that recapitulates the effector/regulatory T cells changes observed in psoriasis will allow for high throughput analysis of potential therapeutic reagents and opens new research opportunities in diseases where regulatory T cells play a role. PUBLIC HEALTH RELEVANCE: The current application proposes to dissect the interplay between protective regulatory T cells, and pathogenic Th1 and Th17 type T cells. A more comprehensive understanding of the relationship between regulatory and pathogenic effector T cells in psoriasis is necessary to gain insight into the mechanism(s) of action for drugs already in use for psoriasis, Crohn's and rheumatoid/psoriatic arthritis. Better understanding of the mechanisms for efficacious therapies will help to improve the next generation of therapeutics and identify more tailored targets for intervention.