Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, United States.
Harvard Medical School, Boston, MA, United States.
Front Immunol. 2020 Feb 18;11:171. doi: 10.3389/fimmu.2020.00171. eCollection 2020.
Intranasal mucosal vaccines are an attractive approach to induce protective mucosal immune responses. Activation of lung antigen presenting cells (APCs), a phenotypically and functionally heterogeneous cell population located at distinct mucosal sites, may be key to the immunogenicity of such vaccines. Understanding responsiveness of newborn lung APCs to adjuvants may the inform design of efficacious intranasal vaccines for early life, when most infections occur. Here, we characterized and phenotyped APCs from neonatal (7 days of life) and adult (6-8 weeks of age) mice. Neonatal mice demonstrated a relatively high abundance of alveolar macrophages (AMs), with lower percentages of plasmacytoid dendritic cells (pDCs), CD103 (cDC1), and CD11b (cDC2) DCs. Furthermore, neonatal CD103 and CD11b DC subsets demonstrated a significantly lower expression of maturation markers (CD40, CD80, and CD86) as compared to adult mice. Upon stimulation of lung APC subsets with a panel of pattern recognition receptor (PRR) agonists, including those engaging TLRs or STING, CD11c enriched cells from neonatal and adult mice lungs demonstrated distinct maturation profiles. Of the agonists tested, the TLR5 ligand, flagellin, was most effective at activating neonatal lung APCs, inducing significantly higher expression of maturation markers on CD103 (cDC1) and CD11b (cDC2) subsets. Intranasal administration of flagellin induced a distinct migration of CD103 and CD11b DC subsets to the mediastinal lymph nodes (mLNs) of neonatal mice. Overall, these findings highlight age-specific differences in the maturation and responsiveness of lung APC subsets to different PRR agonists. The unique efficacy of flagellin in enhancing lung APC activity suggests that it may serve as an effective adjuvant for early life mucosal vaccines.
鼻腔黏膜疫苗是诱导保护性黏膜免疫应答的一种有吸引力的方法。激活位于不同黏膜部位的肺抗原呈递细胞（APCs），这是一种表型和功能上不均一的细胞群体，可能是此类疫苗免疫原性的关键。了解新生肺 APC 对佐剂的反应性可能有助于设计针对生命早期（大多数感染发生时）的有效鼻腔疫苗。在这里，我们对来自新生（7 天大）和成年（6-8 周龄）小鼠的 APC 进行了特征描述和表型分析。新生小鼠表现出相对较高丰度的肺泡巨噬细胞（AMs），而浆细胞样树突状细胞（pDCs）、CD103（cDC1）和 CD11b（cDC2）DC 的比例较低。此外，与成年小鼠相比，新生 CD103 和 CD11b DC 亚群的成熟标志物（CD40、CD80 和 CD86）表达水平显著降低。在用一组模式识别受体（PRR）激动剂（包括 TLR 或 STING 激动剂）刺激肺 APC 亚群后，来自新生和成年小鼠肺的 CD11c 富集细胞表现出不同的成熟谱。在测试的激动剂中，TLR5 配体 flagellin 最有效地激活新生肺 APC，诱导 CD103（cDC1）和 CD11b（cDC2）亚群上成熟标志物的表达显著增加。鼻内给予 flagellin 可诱导 CD103 和 CD11b DC 亚群向新生小鼠的纵隔淋巴结（mLNs）明显迁移。总的来说，这些发现强调了肺 APC 亚群对不同 PRR 激动剂的成熟和反应性存在年龄特异性差异。Flagellin 在增强肺 APC 活性方面的独特功效表明，它可能是生命早期黏膜疫苗的有效佐剂。
