Vargas-Inchaustegui Diego A, Demers Andrew, Shaw Julia M, Kang Guobin, Ball David, Tuero Iskra, Musich Thomas, Mohanram Venkatramanan, Demberg Thorsten, Karpova Tatiana S, Li Qingsheng, Robert-Guroff Marjorie
Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583; and.
J Immunol. 2016 Feb 15;196(4):1700-10. doi: 10.4049/jimmunol.1502137. Epub 2016 Jan 15.
Measurement of Ag-specific T follicular helper (TFH) cell activity in rhesus macaques has not previously been reported. Given that rhesus macaques are the animal model of choice for evaluating protective efficacy of HIV/SIV vaccine candidates and that TFH cells play a pivotal role in aiding B cell maturation, quantifying vaccine induction of HIV/SIV-specific TFH cells would greatly benefit vaccine development. In this study, we quantified SIV Env-specific IL-21-producing TFH cells for the first time, to our knowledge, in a nonhuman primate vaccine study. Macaques were primed twice mucosally with adenovirus 5 host range mutant recombinants encoding SIV Env, Rev, Gag, and Nef followed by two i.m. boosts with monomeric SIV gp120 or oligomeric SIV gp140 proteins. At 2 wk after the second protein boost, we obtained lymph node biopsy specimens and quantified the frequency of total and SIV Env-specific IL-21(+) TFH cells and total germinal center B cells, the size and number of germinal centers, and the frequency of SIV-specific Ab-secreting cells in B cell zones. Multiple correlation analyses established the importance of TFH for development of B cell responses in systemic and mucosally localized compartments, including blood, bone marrow, and rectum. Our results suggest that the SIV-specific TFH cells, initially induced by replicating adenovirus-recombinant priming, are long lived. The multiple correlations of SIV Env-specific TFH cells with systemic and mucosal SIV-specific B cell responses indicate that this cell population should be further investigated in HIV vaccine development as a novel correlate of immunity.
此前尚未有关于恒河猴中抗原特异性滤泡辅助性T细胞（TFH）活性测量的报道。鉴于恒河猴是评估HIV/SIV疫苗候选物保护效力的首选动物模型，且TFH细胞在辅助B细胞成熟中起关键作用，对HIV/SIV特异性TFH细胞的疫苗诱导进行定量将极大地有益于疫苗开发。在本研究中，据我们所知，在一项非人灵长类疫苗研究中，我们首次对SIV Env特异性产生IL-21的TFH细胞进行了定量。猕猴经黏膜用编码SIV Env、Rev、Gag和Nef的腺病毒5宿主范围突变重组体进行两次免疫，随后用单体SIV gp120或寡聚体SIV gp140蛋白进行两次肌肉注射加强免疫。在第二次蛋白加强免疫后2周，我们获取了淋巴结活检标本，并对总的和SIV Env特异性IL-21(+) TFH细胞的频率、生发中心B细胞总数、生发中心的大小和数量以及B细胞区中SIV特异性抗体分泌细胞的频率进行了定量。多重相关性分析确定了TFH对于全身和黏膜局部区室（包括血液、骨髓和直肠）中B细胞反应发展的重要性。我们的结果表明，最初由复制型腺病毒重组体免疫诱导产生的SIV特异性TFH细胞寿命较长。SIV Env特异性TFH细胞与全身和黏膜SIV特异性B细胞反应之间的多重相关性表明，在HIV疫苗开发中应进一步研究这一细胞群体，将其作为一种新的免疫相关指标。
