Université Paris Descartes, Faculté de Médecine-Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Hôpital Necker, Paris, France.
J Immunol. 2011 Jan 1;186(1):284-90. doi: 10.4049/jimmunol.1001348. Epub 2010 Dec 3.
It has been documented that TLR7 stimulation triggers not only antiviral responses, but also alleviates experimental asthma. Considering the implication of invariant NKT (iNKT) cells in both situations, we postulated that they might contribute to the anti-inflammatory effect of TLR7 ligands. We show in this study that spleen cells activated by the TLR7 agonist resiquimod (R848) attenuate allergic inflammation upon adoptive transfer when they are recovered from wild-type, but not from iNKT cell-deficient Jα18(-/-) mice, which proves the specific involvement of this regulatory population. Furthermore, we provide evidence that IFN-γ is critical for the protective effect, which is lost when transferred iNKT cells are sorted from IFN-γ-deficient mice. In support of a direct activation of iNKT cells through TLR7 signaling in vivo, we observed a prompt increase of serum IFN-γ levels, associated with upregulation of CD69 expression on iNKT cells. Moreover, we demonstrate that iNKT cells effectively express TLR7 and respond to R848 in vitro by producing high levels of IFN-γ in the presence of IL-12, consistent with the conclusion that their contribution to the alleviation of allergic inflammation upon treatment with TLR7 ligands is mediated through IFN-γ.
有文献记载 TLR7 刺激不仅能引发抗病毒反应，还能缓解实验性哮喘。鉴于不变自然杀伤 T(iNKT)细胞在这两种情况下的作用，我们假设它们可能有助于 TLR7 配体的抗炎作用。在这项研究中，我们发现 TLR7 激动剂瑞喹莫德（R848）激活的脾细胞在从野生型而非 iNKT 细胞缺陷型 Jα18(-/-)小鼠中回收时，通过过继转移可减轻过敏炎症，这证明了这种调节性群体的特异性参与。此外，我们提供的证据表明 IFN-γ 对于保护作用至关重要，当从 IFN-γ 缺陷型小鼠中转移的 iNKT 细胞被分选时，这种保护作用就会丧失。为了支持 TLR7 信号在体内直接激活 iNKT 细胞，我们观察到血清 IFN-γ 水平的迅速升高，同时 iNKT 细胞上 CD69 表达上调。此外，我们证明 iNKT 细胞在体外有效表达 TLR7，并在 IL-12 的存在下对 R848 产生高水平的 IFN-γ，这与它们通过 TLR7 配体治疗缓解过敏炎症的贡献是通过 IFN-γ 介导的结论一致。
