Department of Medicine, Harvard Medical School and Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Immunol. 2010 Jan 15;184(2):1003-13. doi: 10.4049/jimmunol.0900877. Epub 2009 Dec 4.
We previously established that the inhibitory receptor LILRB4 mitigates LPS-induced, neutrophil-dependent pathologic effector mechanisms in inflammation. We now report that LILRB4 on dendritic cells (DCs) counterregulates development of an adaptive Th2 immune response and ensuing inflammation in a model of allergic pulmonary inflammation, initiated by inhalation sensitization with OVA and LPS followed by airway challenge with OVA. We found that Lilrb4(-/-) mice had significantly exacerbated eosinophilic pulmonary inflammation, as assessed in bronchoalveolar lavage and lung tissue, as well as elevated levels of OVA-specific IgE and Th2 cytokines produced by OVA-restimulated lymph node cells. LILRB4 was preferentially expressed on MHC class II(high)CD86(high) OVA-bearing DCs in lung-draining lymph nodes after sensitization or challenge. Moreover, the lymph nodes of Lilrb4(-/-) mice had significantly more of these mature DCs after challenge with OVA, which was accompanied by significantly more IL-4-producing lymphocytes, compared with Lilrb4(+/+) mice. Sensitization of naive Lilrb4(+/+) mice by transfer of OVA-LPS-pulsed Lilrb4(-/-) bone marrow-derived DCs was sufficient to confer exacerbated allergic lung pathology upon challenge with OVA, compared with mice that received Lilrb4(+/+) bone marrow-derived DCs. Our findings establish that maturation and migration of pulmonary DCs to lymph nodes in response to Ag and an innate immune stimulus is associated with upregulated expression of LILRB4. In addition, this receptor attenuates the number of these mature DCs and attendant IL-4-producing lymphocytes in the lymph nodes, and accordingly, the ability of DCs to elicit pathologic Th2 pulmonary inflammation.
我们之前已经证实抑制性受体 LILRB4 可以减轻 LPS 诱导的中性粒细胞依赖的炎症病理性效应机制。我们现在报告称，树突状细胞（DC）上的 LILRB4 可在过敏肺炎症模型中调节适应性 Th2 免疫反应的发展和随之而来的炎症，该模型通过用 OVA 和 LPS 吸入致敏，然后用 OVA 气道挑战引发。我们发现，Lilrb4(-/-) 小鼠的嗜酸性粒细胞性肺炎症明显加重，通过支气管肺泡灌洗和肺组织评估，OVA 特异性 IgE 和由 OVA 刺激的淋巴结细胞产生的 Th2 细胞因子水平也升高。在致敏或挑战后，LILRB4 优先表达在肺引流淋巴结中 MHC Ⅱ类（高）CD86（高）OVA 负载的 DC 上。此外，与 Lilrb4(+/+) 小鼠相比，Lilrb4(-/-) 小鼠在接受 OVA 挑战后，这些成熟 DC 数量明显更多，并且与它们相比，IL-4 产生的淋巴细胞也明显更多。用 OVA-LPS 脉冲的 Lilrb4(-/-) 骨髓来源的 DC 转染 naive Lilrb4(+/+) 小鼠足以在接受 OVA 挑战时赋予更严重的过敏肺病理，与接受 Lilrb4(+/+) 骨髓来源的 DC 的小鼠相比。我们的研究结果表明，Ag 和先天免疫刺激物引起的肺 DC 向淋巴结的成熟和迁移与 LILRB4 的上调表达有关。此外，该受体减少了这些成熟 DC 的数量以及伴随的淋巴结中 IL-4 产生的淋巴细胞，因此，DC 引发病理性 Th2 肺炎症的能力也受到影响。
