An Essential Role for C5aR Signaling in the Optimal Induction of a Malaria-Specific CD4+ T Cell Response by a Whole-Killed Blood-Stage Vaccine
An Essential Role for C5aR Signaling in the Optimal Induction of a Malaria-Specific CD4+ T Cell Response by a Whole-Killed Blood-Stage Vaccine
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DOI：
10.4049/jimmunol.1201190
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发表时间：
2013-07-01
影响因子：
4.4
通讯作者：
Xu, Wenyue
中科院分区：
文献类型：
--
作者：
Liu, Taiping;Xu, Guilian;Xu, Wenyue
疟原虫全灭活疫苗诱导的抗疟原虫血液期感染的保护性免疫依赖于CD 4（+）T细胞应答。然而，这种强大的CD 4（+）T细胞反应的机制引起的全杀寄生虫疫苗仍然是未知的。在这项研究中，我们观察到约氏疟原虫寄生的红细胞裂解物免疫激活补体C5和产生C5 a。然而，对约氏疟原虫17 XL攻击的保护效力显著降低，并且在C5 aR缺陷（C5 aR（-/-））小鼠中疟疾特异性CD 4（+）T细胞活化和记忆T细胞分化被极大地抑制。过继转移试验表明，C5 aR（-/-）小鼠的保护作用降低与严重受损的CD 4（+）T细胞应答密切相关。这一点通过以下事实进一步证实：施用C5 aR拮抗剂显著降低了免疫的B细胞缺陷小鼠的保护效力。进一步的研究表明，C5 aR（-/-）小鼠中缺陷的CD 4（+）T细胞应答不太可能参与CD 4（+）CD 25（+）Foxp 3（+）T细胞的扩增，但与树突状细胞（DC）成熟缺陷和同种异体刺激CD 4（+）T细胞的能力密切相关。这些结果表明，C5 aR信号通路通过调节DCs的功能，对疟原虫全灭活疫苗诱导的疟疾特异性CD 4（+）T细胞应答的最佳诱导是必不可少的，这为我们设计有效的血液期亚单位疫苗提供了新的线索，并有助于我们理解补体系统调节T细胞应答的机制。免疫学杂志，2013，191：178-186。
The protective immunity induced by the whole-killed parasite vaccine against malarial blood-stage infection is dependent on the CD4(+) T cell response. However, the mechanism underlying this robust CD4(+) T cell response elicited by the whole-killed parasite vaccine is still largely unknown. In this study, we observe that immunization with Plasmodium yoelii-parasitized RBC lysate activates complement C5 and generates C5a. However, the protective efficacy against P. yoelii 17XL challenge is considerably reduced, and the malaria-specific CD4(+) T cell activation and memory T cell differentiation are largely suppressed in the C5aR-deficient (C5aR(-/-)) mice. An adoptive transfer assay demonstrates that the reduced protection of C5aR(-/-) mice is closely associated with the severely impaired CD4(+) T cell response. This is further confirmed by the fact that administration of C5aR antagonist significantly reduces the protective efficacy of the immunized B cell-deficient mice. Further study indicates that the defective CD4(+) T cell response in C5aR(-/-) mice is unlikely involved in the expansion of CD4(+)CD25(+)Foxp3(+) T cells, but strongly linked to a defect in dendritic cell (DC) maturation and the ability to allostimulate CD4(+) T cells. These results demonstrate that C5aR signaling is essential for the optimal induction of the malaria-specific CD4(+) T cell response by the whole-killed parasite vaccine through modulation of DCs function, which provides us with new clues to design an effective blood-stage subunit vaccine and helps us to understand the mechanism by which the T cell response is regulated by the complement system. The Journal of Immunology, 2013, 191: 178-186.