Vaccine-Induced Skewing of T Cell Responses Protects Against Chikungunya Virus Disease
Vaccine-Induced Skewing of T Cell Responses Protects Against Chikungunya Virus Disease
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DOI：
10.3389/fimmu.2019.02563
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发表时间：
2019-10-31
影响因子：
7.3
通讯作者：
Streblow, Daniel N.
中科院分区：
文献类型：
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作者：
Broeckel, Rebecca M.;Haese, Nicole;Streblow, Daniel N.
基孔肯雅病毒（CHIKV）感染可导致严重和衰弱的关节和肌肉疼痛，可能是持久的。目前正在开发的CHIKV疫苗依赖于中和抗体的产生来进行保护;然而，T细胞在控制CHIKV感染和疾病中的作用仍不清楚。使用重叠肽文库，我们鉴定了在感染后7天和14天在C57 BL/6感染的小鼠中识别的CHIKV特异性T细胞受体表位。使用腺病毒和巨细胞病毒载体疫苗表达含有肽451、416、nsP 4的小区域、肽47和HA标签（CHKVf 5）的融合蛋白。用CHKVf 5接种的小鼠引发了比在CHIKV感染后正常观察到的水平更高的稳健的T细胞应答，但疫苗载体不引发中和抗体。当通过肌内CHIKV注射攻击时，CHKVf 5-接种的小鼠具有显著降低的感染性病毒载量。在接种疫苗的小鼠中，CD 4（+）和CD 8（+）T细胞的消耗使它们对肌内CHIKV攻击完全敏感。单独消耗CD 8（+）T细胞降低疫苗效力，尽管程度较小，但仅消耗CD 4（+）T细胞并不逆转保护性表型。这些数据证明了CD 8（+）T细胞在CHIKV感染中的保护作用。然而，通过脚垫接种激发的CHKVf 5疫苗接种小鼠在3 dpi时表现出相等的病毒载量和增加的脚垫肿胀，我们将其归因于疫苗中存在的CD 4 T细胞受体表位。事实上，用仅表达CHIKV特异性CD 8（+）T细胞表位的载体接种小鼠，然后在足垫中进行CHIKV攻击，可预防足垫肿胀，并减少与疾病相关的促炎细胞因子和趋化因子，表明CHIKV特异性CD 8（+）T细胞可预防CHIKV疾病。这些结果还表明，T细胞偏向的预防性疫苗接种方法有效对抗CHIKV攻击并减少小鼠中CHIKV诱导的疾病。
Chikungunya virus (CHIKV) infections can cause severe and debilitating joint and muscular pain that can be long lasting. Current CHIKV vaccines under development rely on the generation of neutralizing antibodies for protection; however, the role of T cells in controlling CHIKV infection and disease is still unclear. Using an overlapping peptide library, we identified the CHIKV-specific T cell receptor epitopes recognized in C57BL/6 infected mice at 7 and 14 days post-infection. A fusion protein containing peptides 451, 416, a small region of nsP4, peptide 47, and an HA tag (CHKVf5) was expressed using adenovirus and cytomegalovirus-vectored vaccines. Mice vaccinated with CHKVf5 elicited robust T cell responses to higher levels than normally observed following CHIKV infection, but the vaccine vectors did not elicit neutralizing antibodies. CHKVf5-vaccinated mice had significantly reduced infectious viral load when challenged by intramuscular CHIKV injection. Depletion of both CD4(+) and CD8(+) T cells in vaccinated mice rendered them fully susceptible to intramuscular CHIKV challenge. Depletion of CD8(+) T cells alone reduced vaccine efficacy, albeit to a lesser extent, but depletion of only CD4(+) T cells did not reverse the protective phenotype. These data demonstrated a protective role for CD8(+) T cells in CHIKV infection. However, CHKVf5-vaccinated mice that were challenged by footpad inoculation demonstrated equal viral loads and increased footpad swelling at 3 dpi, which we attributed to the presence of CD4 T cell receptor epitopes present in the vaccine. Indeed, vaccination of mice with vectors expressing only CHIKV-specific CD8(+) T cell epitopes followed by CHIKV challenge in the footpad prevented footpad swelling and reduced proinflammatory cytokine and chemokines associated with disease, indicating that CHIKV-specific CD8(+) T cells prevent CHIKV disease. These results also indicate that a T cell-biased prophylactic vaccination approach is effective against CHIKV challenge and reduces CHIKV-induced disease in mice.