Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
J Allergy Clin Immunol. 2012 May;129(5):1377-1386.e13. doi: 10.1016/j.jaci.2012.02.035. Epub 2012 Mar 27.
Sensitization to protease allergens, such as papain, or helminth infection is associated with basophil recruitment to draining lymph nodes (LNs). Basophils have the capacity to present antigen to naive T cells and promote T(H)2 differentiation directly or indirectly through IL-4 production.
We studied how papain induces basophil migration to LNs and the contribution of various leukocytes to papain-induced immune responses.
We immunized mice in the footpad with papain and studied leukocyte recruitment and inflammatory cytokine and chemokine production in the draining popliteal LNs.
Papain directly activated naive T cells through protease-activated receptor (PAR) 2 to initiate a chemokine/cytokine program that includes CCL17, CCL22, and IL-4. Papain-triggered innate immune responses were dependent on both CD4 T cells and PAR2 and were strongly reduced in the absence of CCR4, the primary receptor for CCL17/CCL22.
These results elucidate a novel innate allergen-recognition pathway mediated by naive T cells through PAR2, which provide an immediate source of chemokines and IL-4 upstream of basophils and antigen-restricted T(H)2 differentiation. PAR2 antagonism might thus hold promise for the treatment of allergic disease.
对蛋白酶过敏原（如木瓜蛋白酶）的致敏或寄生虫感染与嗜碱性粒细胞向引流淋巴结（LN）的募集有关。嗜碱性粒细胞具有向幼稚 T 细胞呈递抗原的能力，并通过 IL-4 产生直接或间接促进 T(H)2 分化。
我们研究了木瓜蛋白酶如何诱导嗜碱性粒细胞迁移到 LNs，以及各种白细胞对木瓜蛋白酶诱导的免疫反应的贡献。
我们通过足底注射木瓜蛋白酶对小鼠进行免疫，并研究引流的腘淋巴结中白细胞募集和炎症细胞因子和趋化因子的产生。
木瓜蛋白酶通过蛋白酶激活受体（PAR）2 直接激活幼稚 T 细胞，启动包括 CCL17、CCL22 和 IL-4 在内的趋化因子/细胞因子程序。木瓜蛋白酶触发的固有免疫反应依赖于 CD4 T 细胞和 PAR2，并且在缺乏 CCR4（CCL17/CCL22 的主要受体）的情况下大大减少。
这些结果阐明了一种通过 PAR2 介导的幼稚 T 细胞介导的新型先天过敏原识别途径，为嗜碱性粒细胞和抗原限制性 T(H)2 分化之前的趋化因子和 IL-4 提供了即时来源。因此，PAR2 拮抗剂可能为治疗过敏疾病提供希望。
