Papillomavirus-Specific CD4+ T Cells Exhibit Reduced STAT-5 Signaling and Altered Cytokine Profiles in Patients with Recurrent Respiratory Papillomatosis
Papillomavirus-Specific CD4+ T Cells Exhibit Reduced STAT-5 Signaling and Altered Cytokine Profiles in Patients with Recurrent Respiratory Papillomatosis
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DOI：
10.4049/jimmunol.1004181
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发表时间：
2011-06-01
影响因子：
4.4
通讯作者：
Bonagura, Vincent R.
中科院分区：
文献类型：
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作者：
James, Eddie A.;DeVoti, James A.;Bonagura, Vincent R.
复发性呼吸道乳头状瘤病是由人乳头瘤病毒6型(HPV-6)或HPV-11引起的。特定的人类白细胞抗原-DR单倍型DRB1*01：02和DRB1*03：01与RRP的发生、疾病严重程度以及对HPV早期蛋白的Th2样反应有关。在动物模型中，对HPV蛋白的Th1样反应被证明是保护性的。因此，我们调查了RRP患者有功能障碍的Th1样HPV特异性T细胞反应的假设。利用MHC-II类四聚体，我们鉴定了HPV-11早期蛋白中的免疫原肽。E6(113-132)和E2(1-20)分别含有DRB1*01：02-或DRB1*03：01-限制性表位。一个额外的多肽(E2(281-300))包含两个等位基因呈现的表位。多肽结合、四聚体和增殖试验确定了这些多肽中的最小表位。这些表位在RRP患者和健康对照组中激发了E2/E6特异性的CD4(+)T细胞反应，允许使用四聚体分离HPV特异性T细胞株。测量这些四聚体阳性T细胞的细胞因子谱和STAT信号，以比较来自RRP患者和健康受试者的HPV特异性T细胞的极化和反应性。RRP患者T细胞中HPV特异性干扰素-γ的分泌显著降低。在RRP患者的T细胞中可见适度的HPV特异性IL-13分泌，而在健康对照组的T细胞中未见HPV特异性IL-13分泌。来自RRP患者的HPV特异性T细胞表现出STAT-5磷酸化降低和IL-2分泌减少，提示无能。在RRP患者的HPV特异性T细胞系中加入IL-2可以提高STAT-5的磷酸化水平和干扰素-γ的分泌水平。治疗性疫苗接种或旨在恢复对HPV蛋白的Th1样细胞因子反应和逆转无能的干预措施可以改善RRP患者的临床结果。免疫学杂志，2011,186：6633-6640。
Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus type 6 (HPV-6) or HPV-11. Specific HLA-DR haplotypes DRB1*01:02 and DRB1*03:01 are associated with the development of RRP, disease severity, and Th2-like responses to HPV early proteins. Th1-like responses to HPV proteins have been shown to be protective in animal models. Therefore, we investigated the hypothesis that RRP patients have dysfunctional Th1-like, HPV-specific T cell responses. Using MHC class II tetramers, we identified immunogenic peptides within HPV-11 early proteins. Two distinct peptides (E6(113-132) and E2(1-20)) contained DRB1*01:02- or DRB1*03:01-restricted epitopes, respectively. An additional peptide (E2(281-300)) contained an epitope presented by both alleles. Peptide binding, tetramer, and proliferation assays identified minimal epitopes within these peptides. These epitopes elicited E2/E6-specific CD4(+) T cell responses in RRP patients and healthy control subjects, allowing the isolation of HPV-specific T cell lines using tetramers. The cytokine profiles and STAT signaling of these tetramer-positive T cells were measured to compare the polarization and responsiveness of HPV-specific T cells from patients with RRP and healthy subjects. HPV-specific IFN-gamma secretion was substantially lower in T cells from RRP patients. HPV-specific IL-13 secretion was seen at modest levels in T cells from RRP patients and was absent in T cells from healthy control subjects. HPV-specific T cells from RRP patients exhibited reduced STAT-5 phosphorylation and reduced IL-2 secretion, suggesting anergy. Levels of STAT-5 phosphorylation and IFN-gamma secretion could be improved through addition of IL-2 to HPV-specific T cell lines from RRP patients. Therapeutic vaccination or interventions aimed at restoring Th1-like cytokine responses to HPV proteins and reversing anergy could improve clinical outcomes for RRP patients. The Journal of Immunology, 2011, 186: 6633-6640.