Immune Regulation of Extrathymic T (NK1.1^+T) Cells in Parasitic Infection

在最近的一系列研究中，我们已经证明肝脏是一个重要的免疫器官，在小鼠和人类中产生胸腺外T细胞。这些T细胞在许多特性上区别于胸腺源性T细胞。其中一些特性包括TCR-CD3复合物在其表面的中等密度和白介素- 2rβ链的组成表达。对寄生虫感染的保护性免疫的发展需要T细胞的存在。在本项目中，我们研究了腺外T细胞在小鼠感染小鼠疟疾（p.j oelli）、利什曼原虫（l.s major）和蛔虫幼虫（T.canis）时的作用。1)内脏幼虫迁移模型在犬绦虫感染早期（第1天），观察到独特的肝脏T细胞群，即双阳性（DP） CD4^+CD8^+细胞。胸腺外T细胞的比例也随之升高。2)利什曼病模型感染L.major后，小鼠肝脏胸腺外T细胞水平升高。肝脏中这些T细胞中IL-4的产量升高。这些结果表明，小鼠利什曼病主要诱导Th2型免疫应答。3)小鼠疟疾模型用流式细胞术分析小鼠肝脏、脾脏和胸腺淋巴细胞，观察胸腺外T细胞的扩增。它们对被寄生的红细胞具有自反应性和细胞毒性。TL-2Rbeta^+细胞的缺失导致非致死性疟疾菌株感染的早期加重。这些数据表明胸腺外T细胞在啮齿动物疟疾感染的红细胞阶段发挥作用。这些结果表明，在寄生虫感染过程中，各器官中胸腺外T细胞的扩增在保护性免疫中起着重要作用。

In a series of recent studies, we have demonstrated that the liver is an important immune organs that produces extrathymic T cells in mice and humans. These T cells are distinguished from thymus-derived T cells by many properties. Some of these properties include the intermediate density of TCR-CD3 complex on their surface and constitutive expression of interleukin-2Rbeta-chain.The development of protective immunity to parasitic infection requires the presence of T cells. In this project, we investigated the role of extrathyinic T cells in mice during infection with murine malaria (P.yoelli), Leishmania (L.major) and Ascaris larvae (T.canis).1) Visceral larva migrans model In early phase of T.canis infection (on day 1), unique population of hepatic T cells were observed, i.e., double-positive (DP) CD4^+CD8^+ cells. The proportion of extrathymic T cells was also elevated therafter.2) Leishmaniasis model In mice infected with L.major, the levels of extrathymic T cells in the liver increased. The produciblity of IL-4 in these T cells elevated in the liver. These observations indicate that the induction of Th2 type immune response is dominant in murine Leishmaniasis.3) Murine malaria model Expansion of extrathymic T cells were observed with flowcytometric analysis of lymphocytes from liver, spleen and thymus. They possessed self-reactive forbidden clones and cytotoxicity against parasitized RBC.Deletion of TL-2Rbeta^+ cells resulted in early exacerbation of infection of the non-lethal strain malaria. These data indicate the extrathymic T cells play a role during the erythrocytic stage of the rodent malaria infection.These results suggest that the expanding extrathymic T cells in various organs play an important role of protective immunity during parasitic infection.