School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Pediatr Allergy Immunol. 2019 Aug;30(5):531-539. doi: 10.1111/pai.13061. Epub 2019 May 30.
4-1BB (CD137), a member of the inducible tumor necrosis factor receptor (TNFR) family, is expressed on regulatory T (Treg) cells and regulates Treg cells to control allergic inflammation. Pam3CSK4, a synthetic TLR2 ligand that can expand CD8 Treg function, is a promising adjuvant for allergen immunotherapy (IT). We examined whether Dermatophagoides pteronyssinus (Der p) IT and Pam3CSK4 could enhance CD8 CD25 CD137 Treg suppressive function to decrease nasal nitric oxide (nNO) levels.
Nasal symptom scores, nNO levels, PBMCs, and inferior turbinate biopsies were obtained from 40 mite-sensitive perennial allergic rhinitis (PAR) patients before and after one year of Der p IT and 30 non-allergic control subjects. CD137 expression on CD8 CD25 T cells and suppressive function of CD8 CD25 CD137 Tregs was measured using flow cytometry. Cytokine levels were analyzed by ELISA. Inducible nitric oxide synthase production by nasal epithelial cells after co-culturing with CD8 CD25 CD137 T cells was analyzed by Western blotting.
Der p IT improved nasal symptom scores, decreased nNO levels, and increased CD137 expression on CD8 T cells in PBMCs and nasal mucosa. Pam3CSK4 expanded the CD8 CD25 CD137 population in PBMCs. Pam3CSK4-stimulated CD8 CD25 CD137 Tregs induced IL-10 and TGF-β and suppressed CD4 CD25- T-cell proliferation mainly by cell contact inhibition. CD8 CD25 CD137 Tregs cultured with nasal epithelial cells suppressed Der p 2-induced iNOS production. Silencing CD137 in sorted CD8 CD25 T cells decreased Pam3CSK4-activated Foxp3 expression.
Der p IT expanded CD8 CD25 CD137 Tregs and decreased nNO levels. Induced CD137 expression on CD8 CD25 Tregs by Pam3CSK4 stimulation may help suppress allergic inflammation during IT.
4-1BB（CD137）是诱导型肿瘤坏死因子受体（TNFR）家族的成员，在调节性 T（Treg）细胞上表达，并调节 Treg 细胞以控制过敏炎症。Pam3CSK4 是一种合成的 TLR2 配体，可扩增 CD8 Treg 功能，是变应原免疫治疗（IT）的有前途的佐剂。我们研究了尘螨（Der p）IT 和 Pam3CSK4 是否可以增强 CD8+CD25+CD137+Treg 的抑制功能，以降低鼻一氧化氮（nNO）水平。
从 40 例尘螨敏感的常年性过敏性鼻炎（PAR）患者和 30 例非过敏性对照者在接受 Der p IT 治疗前后一年，分别获得鼻症状评分、nNO 水平、PBMC 和下鼻甲活检。使用流式细胞术测量 CD8+CD25+T 细胞上的 CD137 表达和 CD8+CD25+CD137+Treg 的抑制功能。通过 ELISA 分析细胞因子水平。通过 Western blot 分析鼻上皮细胞与 CD8+CD25+CD137+T 细胞共培养后诱导型一氧化氮合酶的产生。
Der p IT 改善了鼻症状评分，降低了 nNO 水平，并增加了 PBMC 和鼻黏膜中 CD8 细胞上的 CD137 表达。Pam3CSK4 扩增了 PBMC 中的 CD8+CD25+CD137 群体。Pam3CSK4 刺激的 CD8+CD25+CD137+Treg 诱导了 IL-10 和 TGF-β，并通过细胞接触抑制主要抑制 CD4+CD25-T 细胞增殖。与鼻上皮细胞共培养的 CD8+CD25+CD137+Treg 抑制了 Der p2 诱导的 iNOS 产生。在分选的 CD8+CD25+T 细胞中沉默 CD137 降低了 Pam3CSK4 激活的 Foxp3 表达。
Der p IT 扩增了 CD8+CD25+CD137+Treg 并降低了 nNO 水平。Pam3CSK4 刺激 CD8+CD25+T 细胞诱导的 CD137 表达可能有助于抑制 IT 期间的过敏炎症。
