Major Histocompatibility Complex Class I–Restricted Infiltration and Destruction of Pancreatic Islets by NOD Mouse-Derived β-Cell Cytotoxic CD8+ T-Cell Clones In Vivo
Major Histocompatibility Complex Class I–Restricted Infiltration and Destruction of Pancreatic Islets by NOD Mouse-Derived β-Cell Cytotoxic CD8+ T-Cell Clones In Vivo
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DOI：
10.2337/diab.45.8.1121
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发表时间：
1996-08
期刊：
影响因子：
7.7
通讯作者：
T. Utsugi;J. Yoon;Byung-Ju Park;M. Imamura;N. Averill;S. Kawazu;P. Santamaria
中科院分区：
文献类型：
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作者：
T. Utsugi;J. Yoon;Byung-Ju Park;M. Imamura;N. Averill;S. Kawazu;P. Santamaria
NOD小鼠来源的β细胞特异性细胞毒性T细胞（β-CTL）克隆在成年NOD小鼠中具有致糖尿病性，但仅当与来自糖尿病动物的脾CD 4 + T细胞共注射时才具有致糖尿病性。本研究旨在确定β-CTL对胰岛的浸润是否是主要组织相容性复合体（MHC）I类限制性反应，以及β-CTL是否对体内β细胞具有直接的细胞病变作用。将来自BALB/c（H-2d）或B6（H-2 B）小鼠的胰岛分别移植到链脲佐菌素（STZ）诱导的糖尿病（NOD × BALB/c）F1（H-2Kd，H-2Dd，B）或（NOD × B6）F1（H-2Kd，B，H-2D B）小鼠的肾包膜下。在移植后3天内将NOD小鼠的H-2Kd限制性β-CTL克隆输入血糖正常的小鼠体内。在所有接受β-CTL克隆的H-2d胰岛移植（NOD × BALB/c）F1小鼠中，β-CTL归巢到移植物中，募集宿主Mac-1+细胞和CD 4+和CD 8 + T细胞，并在7天内引起糖尿病。相反，接受β-CTL克隆的H-2b胰岛移植（NOD × B6）Fl小鼠和接受非β细胞毒性CTL克隆（Nβ-CTL）的H-2d胰岛移植（NOD × BALB/c）Fl小鼠均未发生移植物炎症或糖尿病。在H-2d胰岛移植（NOD × BALB/c）F1小鼠中，CD 4 + T细胞的耗竭不能预防β-CTL克隆诱导的糖尿病，但能降低其严重程度。相反，当β-CTL克隆在移植后>8天注射时，没有H-2d胰岛移植（NOD × BALB/c）F1小鼠变成糖尿病或发生移植物炎症。我们的结论是：（1）胰岛源性β-CTL可以在体内破坏β细胞;（2）β-CTL对移植胰岛的浸润是一种MHC I类限制性反应;（3）β-CTL可以将初始CD 4 + T细胞募集到该部位，导致进一步的β细胞损伤;（4）血运重建的胰岛移植物与受辐射的成年NOD小鼠的胰岛一样，与循环β-CTL“隔离”。
NOD mouse-derived β-cell-specific cytotoxic T-cell (β-CTL) clones are diabetogenic in adult NOD mice, but only if co-injected with splenic CD4+ T-cells from diabetic animals. This investigation was initiated to determine whether infiltration of pancreatic islets by β-CTL is a major histocompatibility complex (MHC) class I-restricted response, and whether β-CTL has a direct cytopathic effect on β-cells in vivo. Pancreatic islets from BALB/c (H-2d) or B6 (H-2b) mice were transplanted under the renal capsule of streptozotocin (STZ)-induced diabetic (NOD × BALB/c) Fl (H-2Kd, H-2Dd,b) or (NOD × B6) Fl (H-2Kd,b, H-2Db) mice, respectively. H-2Kd-restricted β-CTL clones from NOD mice were transfused into euglycemic mice within 3 days after transplantation. In all of the H-2d islet-grafted (NOD × BALB/c) Fl mice that received the β-CTL clones, the β-CTLs homed into the grafts, recruited host Mac-1+ cells and CD4+ and CD8+ T-cells, and caused diabetes within 7 days. In contrast, none of the H-2b islet-grafted (NOD × B6) Fl mice who received the β-CTL clones and none of the H-2d islet-grafted (NOD × BALB/c) Fl mice who received a non-β-cell cytotoxic CTL clone (Nβ-CTL) developed graft inflammation or diabetes. Depletion of CD4+ T-cells in H-2d islet-grafted (NOD × BALB/c) Fl mice did not prevent β-CTL clone-induced diabetes but reduced its severity. In contrast, when the β-CTL clones were injected >8 days after transplantation, none of the H-2d islet-grafted (NOD × BALB/c) Fl mice became diabetic or developed graft inflammation. We conclude that (1) isletderived β-CTLs can destroy β-cells in vivo; (2) infiltration of grafted islets by β-CTLs is an MHC class I-restricted response; (3) β-CTLs can recruit naive CD4+ T-cells to the site, leading to further β-cell damage; and (4) revascularized islet grafts are, like pancreatic islets of irradiated adult NOD mice, “sequestered” from circulating β-CTLs.