Xiao Lijun, Wang Dimin, Sun Caijun, Li Pingchao, Jin Yi, Feng Liqiang, Chen Ling
State Key Laboratory of Respiratory Diseases; Guangzhou Institutes of Biomedicine and Health (GIBH); Chinese Academy of Sciences; Guangzhou, PR China; University of Chinese Academy of Sciences; Beijing, PR China.
Hum Vaccin Immunother. 2014;10(3):724-33. doi: 10.4161/hv.27340. Epub 2013 Dec 10.
The development of an effective T cell based HIV vaccine would need to elicit cell mediated immune responses with superior magnitude, breadth, and quality. Since blocking the interactions between inhibitory receptors with their associated ligands using soluble PD-1 (sPD-1) and soluble Tim-3 (sTim-3) have been shown to reverse T cell exhaustion and enhance cell mediated immune responses, we tested if co-administration of sPD-1 and sTim-3 with an adenovirus vectored SIV vaccine (rAd5-SIV) can enhance cell mediated immune responses. The frequency of SIV antigen specific IFN-γ spot-forming cells and the secretion of IFN-γ and TNF-α by splenocytes from rAd5-SIV immunized mice was significantly increased when stimulated ex vivo with SIV peptides in the presence of sPD-1 or sTim-3 or both sPD-1 and sTim-3. The magnitude of cell mediated immune responses elicited by rAd5-SIV was enhanced by co-administration of sPD-1 and sTim-3. Co-administration of both sPD-1 and sTim-3 induced higher frequency of SIV antigen specific IFN-γ(+) spot-forming cells to poorly immunogenic Vif and Tat. The percentage of cell mediated responses for each SIV antigen became more balanced, with reduction to Gag but induction to non-structural proteins. Furthermore, co-injection of rAd5-sPD1 and rAd5-sTim3 with rAd5-SIV in mice enhanced T cell proliferation capability and generated more antigen specific IFN-γ(+) CD4(+) and CD8(+) T cells. Our study provided a new approach to enhance vaccine induced cell mediated immune responses, which may be applicable to improve the efficacy of vaccines against SIV/HIV.
开发一种有效的基于T细胞的HIV疫苗需要引发具有更高强度、广度和质量的细胞介导免疫反应。由于使用可溶性PD-1（sPD-1）和可溶性Tim-3（sTim-3）阻断抑制性受体与其相关配体之间的相互作用已被证明可逆转T细胞耗竭并增强细胞介导免疫反应，我们测试了sPD-1和sTim-3与腺病毒载体SIV疫苗（rAd5-SIV）共同给药是否能增强细胞介导免疫反应。当在sPD-1或sTim-3或两者存在的情况下用SIV肽体外刺激时，来自rAd5-SIV免疫小鼠的脾细胞中SIV抗原特异性IFN-γ斑点形成细胞的频率以及IFN-γ和TNF-α的分泌显著增加。rAd5-SIV引发的细胞介导免疫反应的强度通过sPD-1和sTim-3的共同给药得到增强。sPD-1和sTim-3共同给药诱导了更高频率的SIV抗原特异性IFN-γ(+)斑点形成细胞针对免疫原性较差的Vif和Tat。每种SIV抗原的细胞介导反应百分比变得更加平衡，Gag反应减少而非结构蛋白反应诱导增加。此外，在小鼠中rAd5-sPD1和rAd5-sTim3与rAd5-SIV共同注射增强了T细胞增殖能力并产生了更多抗原特异性IFN-γ(+) CD4(+)和CD8(+) T细胞。我们的研究提供了一种增强疫苗诱导的细胞介导免疫反应的新方法，这可能适用于提高针对SIV/HIV疫苗的效力。
