佐劑MF59對於免疫接種所誘發調節性T細胞建立的影響

Abstract

T細胞疫苗加強對於流感病毒內部相似抗原的T細胞免疫反應，因此T細胞疫苗可以對於不同流感亞型給予保護。然而，亞免疫性T細胞疫苗注射會引發調節性T細胞的產生，這會影響到整體T細胞的免疫力。在使用肽作為疫苗注射時，同時給予類類鐸受體活化佐劑可以抑制調節性T細胞的誘發；但是對於非類類鐸受體活化技佐劑的作用目前仍不清楚。MF59，一個油水混和乳狀液佐劑，是第一個被核准使用在流感病毒疫苗的佐劑。在蛋白質疫苗免疫注射的同時，使用這佐劑可以誘發強烈的中和抗體及具有抗原專一CD4+ T細 胞的免疫反應。目前MF59的作用機制仍不完全清楚，但研究顯示它作用是與類鐸受體完全獨立的。在這篇研究當中，我們使用接受性轉移模式來調查MF59對於具有抗原專一調節性T細胞的誘發及比例擴張。我們發現MF59對於具有抗原專一調節性T細胞的佐劑作用在首次以及二次肽疫苗注射時是不同的。在首次使用肽作為疫苗注射時，同時給予類類鐸受體活化技佐劑不能減少調節性T細胞的比例。然而，它在二次使用肽作為疫苗注射時，會限制具有抗原專一調節性T細胞的比例擴張。除此之外，利用在首次及二次疫苗注射中非致死流感病毒感染及肽作為疫苗注射不同組合搭配的疫苗注射，我們發現首次疫苗注射所引發的免疫反應支配後續調節性T細胞比例擴張的潛力。最後，我們利用peripheral priming-local boosting方法給予老鼠含有MF59佐劑的肽疫苗注射，再給予老鼠致死劑量的流感病毒感染；結果顯示MF59在肽疫苗注射當中只提供了差別不大的生存保護。我們的研究發現MF59對於免疫注射所誘發調節性T細胞的佐劑作用特色讓它成為T細胞疫苗注射策略當中加強疫苗注射時一個值得考慮的佐劑。然而，更多對於它在T細胞免疫影響的研究是被需要的。

T-cell based vaccines, enhancing T cell immune response to the conserved epitope of influenza virus, may provide cross-protective immunity against different viral subtypes. However, subimmunogenic immunization of the T–cell based vaccine may induce regulatory T cell (Treg) development, jeopardizing the T cell immunity. It has been shown that co-administration of the toll-like receptor agonist adjuvants during peptide immunization could reduce Treg induction, but little has been addressed about the non-toll like receptor agonist adjuvants. MF59, an oil in water emulsion adjuvant, is the first approved adjuvant used in the influenza vaccine. It induces profound neutralizing antibodies and antigen-specific CD4+ response after protein-based influenza vaccine immunization. The mechanism of MF59 adjuvanticity is not fully understood, but studies showed that its adjuvanticity reacted in a TLR-independent manner. Herein, we investigated the influence of MF59 on the induction and expansion of antigen-specific Treg using adoptive transfer mice model. We found that the adjuvant effect of MF59 on the Treg development was distinct in primary and secondary peptide immunization. Co-administration of MF59 with the primary peptide immunization could not reduce the antigen-specific Treg proportion. In contrast, it confined the expansion of the antigen-specific Treg proportion in secondary immunization. In addition, heterogenous priming and boosting strategies using non-lethal influenza virus infection and peptide immunization showed that priming immune response dictated the subsequent expansion potential of the Treg. Finally, we immunized the mice with MF59-adjuvanted peptide using peripheral priming-local boosting strategies, and subsequently challenged the mice with lethal-dose influenza virus. Results showed MF59 provided marginal survival benefit in peptide immunization. Our present study demonstrated that the adjuvant effect of MF59 on the vaccination-induced Treg made it a considerable adjuvant for immune boosting instead of priming in T cell vaccine strategy. Nevertheless, further study about its influence on T cell immunity is warranted.