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

在最近的一系列研究中，我们证明了肝脏是小鼠和人类产生胸腺外T细胞的重要免疫器官。这些T细胞与胸腺来源的T细胞有许多不同之处。其中一些特性包括T细胞表面TCR-CD3复合体的中等密度和IL-2Rβ链的结构性表达。对寄生虫感染的保护性免疫需要T细胞的存在。在本研究中，我们研究了胸腺外T细胞在小鼠感染约氏疟原虫(P.yoelli)、大利什曼原虫(L.main)和犬蛔虫幼虫(T.canis)的过程中的作用。1)犬T.canis感染早期(第1天)的内脏幼虫迁移模型中，观察到独特的肝脏T细胞群，即双阳性(DP)的CD4^+CD8^+细胞。感染大鼠利什曼病后，小鼠肝组织中胸腺外T细胞比例升高。肝脏中这些T细胞产生IL-4的能力升高。这些观察结果表明，Th2型免疫应答在小鼠利什曼病中占主导地位。3)用流式细胞仪分析肝、脾和胸腺淋巴细胞，观察小鼠疟疾模型胸腺外T细胞的增殖情况。它们对寄生的红细胞具有自反应性禁用克隆和细胞毒作用，TL-2Rbeta^+细胞的缺失导致非致死性疟疾株感染的早期加重。这些结果表明，胸腺外T细胞在鼠疟原虫感染的红细胞期中起着重要作用。这些结果表明，在寄生虫感染过程中，胸腺外T细胞在各个器官中发挥着重要的保护性免疫作用。

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.