Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice.
Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice.
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DOI：
10.1084/jem.178.1.87
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发表时间：
1993-07-01
期刊：
影响因子：
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通讯作者：
Delovitch TL
中科院分区：
文献类型：
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作者：
Rapoport MJ;Jaramillo A;Zipris D;Lazarus AH;Serreze DV;Leiter EH;Cyopick P;Danska JS;Delovitch TL
从胰岛炎（7周龄）开始，非肥胖糖尿病（NOD）小鼠的CD 4+和CD 8+成熟胸腺细胞在体外T细胞受体（TCR）交联后表现出增殖无反应性。这种无反应性不是由胰岛炎或胸腺退化引起的，而是持久的，即，持续至糖尿病发作（24周龄）。我们以前提出，它代表了一种形式的胸腺T细胞无能，易患糖尿病发作。在本研究中，通过进一步研究NOD胸腺T细胞增殖无反应性的机制，并确定这种无反应性的逆转是否保护NOD小鼠免受糖尿病的影响，来验证这一假设。与在相同条件下刺激的来自年龄和性别匹配的对照BALB/c小鼠的胸腺细胞相比，在用抗TCR α/β、抗CD 3或伴刀豆球蛋白A（Con A）处理后，来自> 7周龄NOD小鼠的胸腺细胞的白细胞介素4（IL-4）分泌几乎检测不到。抗TCR α/β或抗CD 3刺激的NOD胸腺细胞分泌的IL-2比类似活化的BALB/c胸腺细胞分泌的IL-2少。然而，由于ConA激活的NOD和BALB/c胸腺细胞分泌的IL-3水平相当，NOD胸腺T细胞的无反应性似乎并不依赖于IL-2分泌的减少。ConA激活的胸腺细胞的高亲和力IL-2受体的表面密度和解离常数也相似。在抗TCR/CD 3活化的NOD胸腺T细胞中观察到的无反应性和淋巴因子分泌模式也在活化的NOD外周脾T细胞中观察到。外源性重组（r）IL-2仅部分逆转NOD胸腺细胞对抗CD 3的增殖无应答性，这是由IL-2不能刺激完全的IL-4分泌应答介导的。相反，外源性IL-4完全逆转NOD胸腺和外周T细胞的无反应性，这与IL-2分泌反应的完全恢复有关。此外，rIL-4对糖尿病前期NOD小鼠的体内给药保护它们免于糖尿病。因此，rIL-4在体外完全逆转NOD胸腺和外周T细胞增殖缺陷并在体内防止糖尿病的能力进一步支持了NOD小鼠中T细胞增殖无反应性和糖尿病易感性之间的因果关系。
Beginning at the time of insulitis (7 wk of age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This unresponsiveness does not result from either insulitis or thymic involution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that it represents a form of thymic T cell anergy that predisposes to diabetes onset. This hypothesis was tested in the present study by further investigating the mechanism responsible for NOD thymic T cell proliferative unresponsiveness and determining whether reversal of this unresponsiveness protects NOD mice from diabetes. Interleukin 4 (IL-4) secretion by thymocytes from > 7-wk- old NOD mice was virtually undetectable after treatment with either anti-TCR alpha/beta, anti-CD3, or Concanavalin A (Con A) compared with those by thymocytes from age- and sex-matched control BALB/c mice stimulated under identical conditions. NOD thymocytes stimulated by anti-TCR alpha/beta or anti-CD3 secreted less IL-2 than did similarly activated BALB/c thymocytes. However, since equivalent levels of IL-3 were secreted by Con A-activated NOD and BALB/c thymocytes, the unresponsiveness of NOD thymic T cells does not appear to be dependent on reduced IL-2 secretion. The surface density and dissociation constant of the high affinity IL-2 receptor of Con A-activated thymocytes from both strains are also similar. The patterns of unresponsiveness and lymphokine secretion seen in anti-TCR/CD3- activated NOD thymic T cells were also observed in activated NOD peripheral spleen T cells. Exogenous recombinant (r)IL-2 only partially reverses NOD thymocyte proliferative unresponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response. In contrast, exogenous IL-4 reverses the unresponsiveness of both NOD thymic and peripheral T cells completely, and this is associated with the complete restoration of an IL-2 secretion response. Furthermore, the in vivo administration of rIL-4 to prediabetic NOD mice protects them from diabetes. Thus, the ability of rIL-4 to reverse completely the NOD thymic and peripheral T cell proliferative defect in vitro and protect against diabetes in vivo provides further support for a causal relationship between this T cell proliferative unresponsiveness and susceptibility to diabetes in NOD mice.