調節性T細胞與介白素-1在A型流行性感冒病毒感染中生成組織長駐型記憶T細胞的角色

現今施打流行性感冒疫苗所產生的保護性抗體，並無法有效抵抗因抗原漂變或移型所形成的廣泛流感病毒株。而此現象有時會造成區域或全球性流感大流行的發生。然而相對於B細胞所產生的抗體，T細胞因為能辨認流感病毒共有且變異性小的胜肽片段，所以可以有效抵抗廣泛流感病毒株。除此之外，最近研究也指出，組織長駐型記憶T細胞能發出防禦警訊並提供第一線保護。因此，在T細胞疫苗發展研究中，探討哪些因子能促進建立精良的T細胞免疫，特別是在建立組織長駐型記憶T細胞的部分，顯得格外重要。在本篇研究當中，我們將會驗證由先前實驗室觀察而推論出的假說。我們認為介白素-1會經由調控調節性T細胞而阻礙組織長駐型記憶T細胞的生成。而此假說嘗試解釋先前實驗中，介白素-1接受器缺陷鼠有較多組織長駐型記憶T細胞和調節型T細胞，並較能抵抗二次流感病毒感染的現象。在本篇研究中，藉由感染前和感染期間施打白喉毒素的方式，將DEREG小鼠全身的調節型T細胞移除後，我們在感染後第28天觀察到小鼠肺部組織長駐型記憶T細胞組成下降。此觀察現象說明了調節型T細胞具有幫助組織長駐型記憶T細胞建立的特性。同時，介白素-1接受器缺陷的DEREG小鼠以相同策略去除全身的調節性T細胞後，在感染後第28天，其組織長駐型記憶T細胞在肺部的組成比例會與控制組相同，說明了介白素-1會經由調控調節型T細胞而阻礙組織長駐型記憶T細胞的生成。此外，我們也探討介白素-1對於調節型T細胞的影響。藉由未活化的T細胞在感染時受刺激生成能辨認特異抗原的調節型T細胞實驗中，我們觀察到不論介白素-1是直接或間接作用於T細胞，對於能辨認特異抗原的調節型T細胞在感染第7天與第14天的生成並沒有明顯差異。這個現象說明，介白素-1對於調節型T細胞在流感時的早期生成並不是最主要的影響因子。本篇研究主要發現，介白素-1對於組織長駐型記憶T細胞在流感時生成的影響，可能來自於介白素-1對於調節型T細胞的作用。

關鍵字

組織長駐型記憶T細胞；節型T細胞；介白素-1 ；流感病毒

並列摘要

Current inactivated influenza vaccine strategy fails to generate protective antibody to neutralize mutated or heterosubtypic influenza viruses caused by antigenic drift or shift, which sometimes leads to endemic and pandemic burst. In contrast, T cells can recognize conserved viral peptides and thus provide broad cross-protection against heterosubtypic and variant influenza virus. In addition, recent studies have shown that tissue-resident memory T cells (Trm) can serve as an alarm to provide the first-line defense. Thus, studying factors contributing to build up robust T cell immunity, particularly Trm, is critical for development of T cell vaccine. In this study, we examined the hypothesis inferred from our previous observation that IL-1 signaling might suppress the establishment of Trm through modulating regulatory T cells (Treg) and result in interleukin-1 receptor 1 (IL-1R1) deficient mice harboring more Trm and Treg in lung and being more resistant to secondarily heterosubtypic influenza viral infection. By systemic depletion of Treg in DEREG mice with diphtheria toxin (DT) injection prior to and during HKx31 (H3N2) challenge, we observed that the population of Trm decreased in lung at 28 days post-influenza-infection, suggesting that Treg helps establish Trm. Furthermore, depletion of Treg by DT treatment in IL-1R1-/-DEREG mice and DEREG mice harbored a similar level of Trm. This indicated that IL-1 signaling might influence the establishment of Trm through modulating Treg. We also gauged the effects of IL-1 signaling on T cells, either through IL-1 receptor on T cells or through other cells, during influenza A virus infection. Subtle differences of antigen-specific Treg induction were observed at 7 or 14 days post-infection. This observation might indicate that IL-1 signaling might not be the most important factor to induce antigen-specific Treg production during acute influenza A virus infection. We demonstrated Treg would be a possible factor for IL-1R1-deficient mice in building up better Trm. Observations in this study might lead us to unveil the enigma of virus and host interactions and also provide the mechanistic insight into building up optimal T cell vaccine.

並列關鍵字

tissue-resident T cells ； regulatory T cells ； interleukin-1 ； influenza virus

參考文獻

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調節性T細胞與介白素-1在A型流行性感冒病毒感染中生成組織長駐型記憶T細胞的角色

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