重複性低劑量流感病毒的感染對調節性T細胞生成及T細胞免疫系統的影響

The effect of repeated infection of low-dose influenza virus on induction of regulatory T cells and establishment of T cell immunity

芮嵩翔(Sung-Hsiang Jui)

指導教授 ： 楊宏志

國立臺灣大學/醫學院/微生物學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.02356

摘要

流感病毒自1918年的西班牙流感以來，已經造成數次的大流行，最近一次是2009年新型流感的大流行，造成大流行的流感病毒能迅速在全世界傳播，並造成許多重症或致死病例現今的流感疫苗，以不活化的病毒為主，能刺激免疫系統中的B 細胞產生辨認病毒外鞘蛋白質的中和抗體，並有效的預防相同或極為相似的病毒株的感染，但由於流感病毒其抗原易於突變，包括抗原飄移與抗原移型，使得目前使用的誘發B細胞免疫力的疫苗則無法有效預防新的流感病毒株的感染並阻止疫情擴散。
由於T 細胞免疫系統可以辨認病毒的內部蛋白質，造成其在不同株的病毒間有跨株保護的效果，因此如何能夠在流感病毒感染後建立一個良好的且持久的記憶性T細胞免疫系統，是我們所好奇的，而調節性T細胞能影響T細胞免疫力及記憶T細胞的產生，此外，它對於T細胞的擴張，縮減以及記憶三個過程都具有可能的影響效果，也有研究指出調節性T細胞對於T細胞的二次反應具有影響。近年來有研究指出在急性病毒感染之下的確會有調節性T細胞的出現，此外，有研究表示在肺中不斷地以能產生氣喘的抗原刺激後，可以造成調節性T細胞的表現量上升，然而在此所表現出的調節性T細胞並沒有區分究竟是認自身抗原的自然性調節T細胞或是認外來抗原的誘發性調節T細胞，因為誘發性調節T細胞目前在免疫中所扮演的角色比較不明，因此我們對於具有抗原專一性的誘發性調節T細胞非常有興趣，在之前的研究中發現特別是若以低劑量的抗原刺激或避免誘發太強的免疫反應，會造成具有抗原專一性的調節性T細胞的擴增，事實上，在流感的季節，我們有可能反覆接觸到低劑量的流感病毒，因此，我們假設以低劑量的流感病毒重複感染一個個體後,會產生並擴增具有流感病毒抗原專一性的調節性T細胞並抑制之後接續感染不同株流感病毒所誘發的T細胞免疫力，我們初步的研究成果顯示，CD4+FoxP3+調節性T細胞在急性流感病毒感染後確實會在肺部及肺的沖洗液有上升的現象，不過目前並不知道這些上升的調節性T細胞是先天性調節性T細胞或誘發調節性T細胞最後我們設計了幾個實驗方式來看低劑量的流感病毒重複感染一個個體後， 是否會產生調節性T細胞並對T細胞免疫系統造成影響，而在我們的實驗中也確實發現了若是小鼠有先重複感染低劑量的HKx31病毒株，之後再感染高劑量的PR8病毒株，相對於對照組對流感病毒專一辨認的T細胞數目確實有下降的現象， 不過究竟調節性T細胞是否在其中扮演著什麼樣的角色，我們還需要更深入的探討。

關鍵字

調節性T細胞 ； 流感 ； 低劑量 ； 重複感染 ； T細胞免疫力

並列摘要

Since the outbreak of Spanish flu in 1918, there have been several pandemics of influenza A virus. The latest one is the pandemic of 2009 H1N1 influenza A virus. Pandemic influenza A virus usually spreads rapidly across the world, and causes significantly higher morbidity and mortality than seasonal flu virus does. Current influenza virus vaccine can induce robust neutralizing antibody, and effective prevent infection by the same or closed related strain of influenza virus. However, due to high mutation rate of influenza virus, B cell vaccine fails to cope with the emergence of a new strain of influenza virus.
T cells can recognize conserved internal proteins of influenza virus. T cell immunity can provide a “cross-protective” immunity across a broad-spectrum strains of influenza virus. Therefore, we focus on the study of T cell immunity against influenza virus. To establish effective T cell immunity, it is important to understand the factors that affect the generation and maintenance of memory T cell response. Regulatory T cells (Tregs) can regulate T cell immunity, and affect the establishment of T cell memory. Recently, Tregs have been reported to influence T cell immunity induced by acute viral infection and accumulate in the infection site. Besides, Tregs increase in the lung following repeated challenge with antigens. Particularly, low-dose antigen or suboptimal immune stimulation induce more antigen-specific Tregs. Actually, it is possible an individual may have a chance to repeatedly encounter low-dose influenza virus. Therefore, we hypothesize that repeated infection of low-dose influenza virus can induce antigen-specific Tregs, and may suppress the T cell immunity induced by subsequent acute influenza virus infection. Our preliminary result showed that the frequency of CD4+Foxp3+ T cells increased in lung and brochoalveolar lavage (BAL) after acute influenza virus infection. However, we currently do not know whether these influenza virus-induced Tregs are nTregs or influenza virus antigen-specific Tregs. Finally, in a priming and challenge protocol of repeated infection of low-dose influenza virus revealed that, in mice repeatedly primed with low-dose HKx31 strain, the frequency of the influenza virus antigen-specific T cells was reduced after the subsequent challenge with high-dose PR8 strain. However, whether antigen-specific Tregs contribute to this outcome remains further investigating.

並列關鍵字

regulatory T cell ； influenza ； low dose ； repeated infection ； T cell immunity

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