Larocca Rafael A, Provine Nicholas M, Aid Malika, Iampietro M Justin, Borducchi Erica N, Badamchi-Zadeh Alexander, Abbink Peter, Ng'ang'a David, Bricault Christine A, Blass Eryn, Penaloza-MacMaster Pablo, Stephenson Kathryn E, Barouch Dan H
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Microbiology and Immunology, Northwestern University, Chicago, IL 66611, USA.
Sci Immunol. 2016 Nov;1(5). doi: 10.1126/sciimmunol.aaf7643. Epub 2016 Nov 4.
Adenovirus serotype 5 (Ad5) vaccine vectors elicit robust CD8 T cell responses, but these responses typically exhibit a partially exhausted phenotype. However, the immunologic mechanism by which Ad5 vectors induce dysfunctional CD8 T cells has not previously been elucidated. Here we demonstrate that, following immunization of B6 mice, Ad5 vectors elicit antigen-specific IL-10CD4 T cells with a distinct transcriptional profile in a dose-dependent fashion. In rhesus monkeys, we similarly observed upregulated expression of IL-10 and PD-1 by CD4 T cells following Ad5 vaccination. These cells markedly suppressed vaccine-elicited CD8 T cell responses and IL-10 blockade increased the frequency and functionality of antigen-specific CD8 T cells as well as improved protective efficacy against challenge with recombinant . Moreover, induction of these inhibitory IL-10CD4 T cells correlated with IL-27 expression and IL-27 blockade substantially improved CD4 T cell functionality. These data highlight a role for IL-27 in the induction of inhibitory IL-10CD4 T cells, which suppress CD8 T cell magnitude and function following Ad5 vector immunization. A deeper understanding of the cytokine networks and transcriptional profiles induced by vaccine vectors should lead to strategies to improve the immunogenicity and protective efficacy of viral vector-based vaccines.
5型腺病毒（Ad5）疫苗载体可引发强烈的CD8 T细胞反应，但这些反应通常表现出部分耗竭的表型。然而，Ad5载体诱导功能失调的CD8 T细胞的免疫机制此前尚未阐明。在此，我们证明，在对B6小鼠进行免疫后，Ad5载体以剂量依赖的方式引发具有独特转录谱的抗原特异性IL-10⁺ CD4 T细胞。在恒河猴中，我们同样观察到Ad5疫苗接种后CD4 T细胞中IL-10和PD-1的表达上调。这些细胞显著抑制了疫苗引发的CD8 T细胞反应，而IL-10阻断增加了抗原特异性CD8 T细胞的频率和功能，同时提高了针对重组病毒攻击的保护效力。此外，这些抑制性IL-10⁺ CD4 T细胞的诱导与IL-27表达相关，而IL-27阻断显著改善了CD4 T细胞的功能。这些数据突出了IL-27在诱导抑制性IL-10⁺ CD4 T细胞中的作用，这些细胞在Ad5载体免疫后会抑制CD8 T细胞的数量和功能。对疫苗载体诱导的细胞因子网络和转录谱的更深入理解应该会带来改善基于病毒载体的疫苗免疫原性和保护效力的策略。
