Single-cell immunoprofiling after immunotherapy for allergic rhinitis reveals functional suppression of pathogenic TH2 cells and clonal conversion
Single-cell immunoprofiling after immunotherapy for allergic rhinitis reveals functional suppression of pathogenic TH2 cells and clonal conversion
复制标题
DOI：
10.1016/j.jaci.2022.06.024
复制
发表时间：
2022-10-04
影响因子：
14.2
通讯作者：
Hanazawa, Toyoyuki
中科院分区：
文献类型：
--
作者：
Iinuma, Tomohisa;Kiuchi, Masahiro;Hanazawa, Toyoyuki
背景：过敏性鼻炎是一个日益严重的问题，在世界范围内。目前唯一能改善该病的治疗方法是抗原特异性免疫治疗，但其作用机制尚不完全清楚。目的：我们全面研究了舌下免疫治疗（SLIT）治疗日本雪松花粉症前后抗原特异性T细胞的作用和变化。我们培养了在开始SLIT之前和之后1年获得的外周血单核细胞，并使用单细胞RNA测序和库测序的组合。为了研究生物标志物，我们使用了来自参与SLIT片剂治疗日本雪松花粉症的2/3期试验的患者的细胞和来自应答良好和不良的门诊患者的细胞。SLIT后的抗原刺激培养导致T（H）2和调节性T细胞的克隆扩增，并且这些CD 4（+）T细胞中的大多数在治疗前后保留了它们的CDR 3区域，表明SLIT导致的抗原特异性克隆应答和分化。然而，SLIT减少了克隆功能性T（H）2细胞的数量，但增加了表达肌球蛋白（MSC）、TGF-β和IL-2的反式T（H）2细胞群。轨迹分析表明SLIT诱导了反式T（H）2细胞向调节性T细胞的克隆分化。结论：单细胞RNA测序和库分析的结合有助于揭示SLIT促进MSC在致病性T（H）2细胞上的表达并抑制其功能的部分潜在机制。MSC可能是变应性鼻炎SLIT的潜在生物标志物。
Background: Allergic rhinitis is a growing problem worldwide. Currently the only treatment that can modify the disease is antigen-specific immunotherapy, but its mechanism of action is not fully understood.Objective: We comprehensively investigated the role and changes of antigen-specific T cells before and after sublingual immunotherapy (SLIT) for Japanese cedar pollinosis.Methods: We cultured peripheral blood mononuclear cells obtained both before and 1 year after initiating SLIT and used a combination of single-cell RNA sequencing and repertoire sequencing. To investigate biomarkers, we used cells frompatients participating a phase 2/3 trial of SLIT tablets for Japanese cedar pollinosis and cells from outpatients with good and poor response.Results: Antigen-stimulated culturing after SLIT led to clonal expansion of T(H)2 and regulatory T cells, and most of these CD4(+) T cells retained their CDR3 regions before and after treatment, indicating antigen-specific clonal responses and differentiation resulting from SLIT. However, SLIT reduced the number of clonal functional T(H)2 cells but increased the trans-type T(H)2 cell population that expresses musculin (MSC), TGF-beta, and IL-2. Trajectory analysis suggested that SLIT induced clonal differentiation of the trans-type T(H)2 cells differentiated into regulatory T cells. Using real-time PCR, we found that the MSC levels increased in the active SLIT group and those with good response after 1 year of treatment.Conclusion: The combination of single-cell RNA sequencing and repertoire analysis helped reveal part of the underlying mechanism: SLIT promotes the expression of MSC on pathogenic T(H)2 cells and suppresses their function. MSC may be a potential biomarker of SLIT for allergic rhinitis.