Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction.
Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction.
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DOI：
10.1016/j.jaci.2016.08.034
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Akbari O
中科院分区：
文献类型：
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作者：
Rigas D;Lewis G;Aron JL;Wang B;Banie H;Sankaranarayanan I;Galle-Treger L;Maazi H;Lo R;Freeman GJ;Sharpe AH;Soroosh P;Akbari O
包括哮喘在内的特应性疾病会加剧2型免疫应答，并涉及许多免疫细胞类型，包括调节性T细胞（TCLs）和新兴的2型先天淋巴细胞（ILC 2）。虽然ILC 2是2型细胞因子的有效生产者，但ILC 2活化和功能的调节尚未得到很好的理解。在本研究中，我们第一次评估了TdR如何与肺ILC 2相互作用并控制其功能。使用体外抑制测定、细胞接触测定和基因表达面板来评估ILC 2和TcB。此外，将人ILC 2和TCL 4过继转移到NOD SCID γ-C缺陷（NSG）小鼠中，给予其同种型或抗ICOS-L抗体，然后用IL-33攻击并评估AHR。我们表明，诱导的TCLs（iTCLs），而不是天然的TCLs（nTCLs），有效地抑制ILC 2驱动的，促炎细胞因子IL-5和IL-13的生产，在体外和体内。从机制上讲，我们的数据揭示了诱导性T细胞共刺激因子（ICOS）的必要性：ICOS-配体细胞接触用于Treg介导的ILC 2抑制，以及抑制性细胞因子TGF-β和IL-10。使用翻译方法，我们然后证明了人iTlR通过ICOS-L抑制同基因人ILC 2以控制人源化ILC 2小鼠模型中的气道炎症。这些发现表明，诱导的Tcl 4的外周扩张可能作为一个有前途的治疗靶点对ILC 2依赖性哮喘。ILC 2上的ICOS-L是哮喘中Treg介导的抑制所必需的。
Atopic diseases including asthma exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T cells (Tregs) and the emerging group 2 innate lymphoid cells (ILC2s). While ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. In the present study, we evaluate for the first time how Tregs interact with pulmonary ILC2s and control their function. ILC2s and Tregs were evaluated using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Tregs were adoptively transferred into NOD SCID gamma-C deficient (NSG) mice, which were given isotype or anti-ICOS-L antibodies, then challenged with IL-33 and assessed for AHR. We show that induced Tregs (iTregs), but not natural Tregs (nTregs), effectively suppress the production of ILC2-driven, pro-inflammatory cytokines IL-5 and IL-13, both in vitro and in vivo. Mechanistically, our data reveal the necessity of Inducible T cell Costimulator (ICOS):ICOS-Ligand cell contact for Treg-mediated ILC2 suppression, alongside suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human iTregs suppress syngeneic human ILC2s via ICOS-L to control airway inflammation in a humanized ILC2 mouse model. These findings suggest that peripheral expansion of induced Tregs may serve as a promising therapeutic target against ILC2-dependent asthma. ICOS-L on ILC2s is required for Treg mediated suppression in asthma.