Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
J Virol. 2024 Oct 22;98(10):e0067724. doi: 10.1128/jvi.00677-24. Epub 2024 Sep 11.
Juvenile-onset recurrent respiratory papillomatosis (JORRP) is caused by persistent infection of epithelial cells by low-risk human papillomavirus (HPV) types 6 and 11. While multiple infiltrated immune cells have been reported to mediate disease progress, knowledge of HPV-reactive T-cell subsets in papillomas remains elusive. Through single-cell RNA sequencing and RNA microarray, we found that CD8+ tissue-resident memory T (CD8+ T) cells with strong interferon-gamma (IFN-γ) production expanded, and were negatively correlated to the disease severity in the frequency of surgery. These IFN-γ+ CD8+ memory T cells were readily activated and expanded by autologous dendritic cells loaded with HPV11 E7 peptide pool. Moreover, T cell receptor (TCR) clonal expansion was observed in JORRP papilloma tissues, indicating a biased TCR repertoire toward HPV-specific recognition. Finally, we identified and characterized HPV11 E7-specific candidate TCR clonotypes from IFN-γ+ CD8+ memory T cells, suggesting their potential application in TCR-engineered T cells (TCR-T) therapy for HPV11-related diseases. Our findings provided insights into the specific local immune response to HPV6/11 infection and highlighted the importance of IFN-γ+ CD8+ T cells in anti-HPV6/11 T-cell immunity.IMPORTANCEThe persistent recurrence of human papillomavirus (HPV) 6/11 infection in papillomas underscores the failure of local immune responses in patients with juvenile-onset recurrent respiratory papillomatosis (JORRP). Our previous study demonstrated that T cells constitute the predominant immune cell population in JORRP papilloma tissues. Understanding the T-cell-mediated immune responses within JORRP papilloma tissues is crucial for disease control. In the present study, we characterized CD8+ tissue-resident memory T (CD8+ T) cells as the primary T-cell subset responsible for local anti-HPV6/11 immunity. Moreover, we identified two HPV11 E7-specific candidate T cell receptor (TCR) clonotypes out of IFN-γ+ CD8+ memory T cells. Overall, our findings provided insights into the local immune responses to HPV6/11 infection and offered information for developing more effective immunotherapeutic strategies against JORRP.
儿童复发性呼吸道乳头瘤病（JORRP）是由低危型人乳头瘤病毒（HPV）6 和 11 型持续感染上皮细胞引起的。虽然已经报道了多种浸润免疫细胞介导疾病进展，但 HPV 反应性 T 细胞亚群在乳头瘤中的知识仍然难以捉摸。通过单细胞 RNA 测序和 RNA 微阵列，我们发现具有强烈干扰素-γ（IFN-γ）产生能力的 CD8+组织驻留记忆 T（CD8+T）细胞扩增，并与手术频率相关疾病严重程度呈负相关。这些 IFN-γ+CD8+记忆 T 细胞可被负载 HPV11E7 肽库的自体树突状细胞轻易激活和扩增。此外，在 JORRP 乳头瘤组织中观察到 T 细胞受体（TCR）克隆扩增，表明 HPV 特异性识别的 TCR 库存在偏向性。最后，我们从 IFN-γ+CD8+记忆 T 细胞中鉴定并表征了 HPV11E7 特异性候选 TCR 克隆型，提示它们在 HPV11 相关疾病的 TCR 工程 T 细胞（TCR-T）治疗中的潜在应用。我们的研究结果提供了 HPV6/11 感染的特定局部免疫反应的见解，并强调了 IFN-γ+CD8+T 细胞在抗 HPV6/11 T 细胞免疫中的重要性。
重要性：HPV6/11 感染在乳头瘤中的持续复发突出了青少年复发性呼吸道乳头瘤病（JORRP）患者局部免疫反应的失败。我们之前的研究表明，T 细胞构成 JORRP 乳头瘤组织中主要的免疫细胞群体。了解 JORRP 乳头瘤组织内的 T 细胞介导的免疫反应对于疾病控制至关重要。在本研究中，我们将 CD8+组织驻留记忆 T（CD8+T）细胞鉴定为负责局部抗 HPV6/11 免疫的主要 T 细胞亚群。此外，我们从 IFN-γ+CD8+记忆 T 细胞中鉴定出两种 HPV11E7 特异性候选 T 细胞受体（TCR）克隆型。总体而言，我们的研究结果提供了 HPV6/11 感染的局部免疫反应的见解，并为开发针对 JORRP 的更有效的免疫治疗策略提供了信息。
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