Division of Rheumatology and Immunology, Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA90033, USA.
J Allergy Clin Immunol. 2012 Aug;130(2):444-52.e7. doi: 10.1016/j.jaci.2012.05.011. Epub 2012 Jun 26.
Induced CD4(+) forkhead box protein 3-positive regulatory T (iTreg) cells are a promising source for cell-based therapies of established inflammatory and autoimmune diseases. However, their relationship to mast cell (MC) function and MC-driven diseases remains unknown.
We sought to explore the roles of iTreg cells on MC function and the established MC-driven disease contact hypersensitivity (CHS).
In vitro coculture studies were carried out to investigate the interaction between iTreg cells in murine or human MCs by using both direct cell-cell contact and transwell systems to separate cell-cell contact. In vivo mice iTreg cells were administered to mice with established CHS, and innate immunologic responses, such as MC infiltration and inflammatory cytokine expression at contact sites, were evaluated.
In vitro coculture under direct cell-cell contact resulted in indirect suppression of IgE-independent activation of MCs by murine or human iTreg cells. Mechanistically, iTreg cells suppressed proinflammatory cytokine levels by modulating nuclear factor κB p65 activation in MCs through T cell-derived TGF-β1. Injection of iTreg cells but not natural CD4(+)CD25(+) regulatory T cells into animals with established CHS resulted in the suppression of infiltration and functions of MCs and also led to decreased production of inflammatory cytokines at allergic contact areas. iTreg cell-mediated immunosuppressive effects were abrogated when iTreg cells were pretreated with TGF-β1 small interfering RNA.
Our study demonstrates that iTreg cells suppress MC function and attenuate established MC-driven CHS through TGF-β1-dependent mechanisms.
诱导的 CD4(+)叉头框蛋白 3 阳性调节性 T(iTreg)细胞是一种有前途的细胞治疗方法，可用于治疗已建立的炎症和自身免疫性疾病。然而，它们与肥大细胞(MC)功能和 MC 驱动的疾病之间的关系尚不清楚。
我们试图探讨 iTreg 细胞对 MC 功能和已建立的 MC 驱动疾病接触过敏(CHS)的作用。
通过直接细胞-细胞接触和 Transwell 系统分离细胞-细胞接触进行体外共培养研究，以研究 iTreg 细胞与鼠或人 MC 之间的相互作用。将体内 iTreg 细胞给予已建立 CHS 的小鼠，并评估接触部位的固有免疫反应，如 MC 浸润和炎症细胞因子表达。
直接细胞-细胞接触下的体外共培养导致鼠或人 iTreg 细胞间接抑制 IgE 非依赖性 MC 激活。从机制上讲，iTreg 细胞通过调节 MC 中的核因子 κB p65 激活来抑制促炎细胞因子水平，从而抑制 MC 中的促炎细胞因子水平。将 iTreg 细胞而不是天然 CD4(+)CD25(+)调节性 T 细胞注入已建立 CHS 的动物中，导致 MC 浸润和功能受到抑制，也导致过敏接触区域炎症细胞因子的产生减少。用 TGF-β1 小干扰 RNA 预处理 iTreg 细胞可消除 iTreg 细胞介导的免疫抑制作用。
我们的研究表明，iTreg 细胞通过 TGF-β1 依赖性机制抑制 MC 功能并减轻已建立的 MC 驱动的 CHS。
