Balasa B, Davies J D, Lee J, Good A, Yeung B T, Sarvetnick N
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 1998 Oct 15;161(8):4420-7.
IL-10 is essential for an early phase of diabetes in nonobese diabetic (NOD) mice, but later becomes protective against its development. The mechanism by which IL-10 mediates the pathway to diabetes in these mice is unknown. Herein, we dissected the cellular and costimulation requirements for diabetes in transgenic (tg) NOD mice that expressed IL-10 in their pancreatic islets (IL-10-NOD mice). We found that IL-10 alone did not cause diabetes because the offspring (IL-10-NOD-scid mice) from back-crosses of IL-10-NOD mice with NOD-scid mice had no diabetes. Moreover, these IL-10-NOD-scid mice were free of lymphocytic infiltration. Treatment of IL-10-NOD mice with depleting anti-CD4 mAb or control mAb had no effect on diabetes. Surprisingly, depletion of CD8+ T cells by treatment with the corresponding mAb inhibited diabetes without attenuating insulitis, demonstrating a critical role for CD8+ T cells in the disease process. Interestingly, B cell-deficient IL-10-NOD mice readily developed diabetes with kinetics and incidence similar to those observed in wild-type mice, demonstrating that B lymphocytes as APCs were not required in the disease process. Administration of anti-CD40 ligand (CD40L) mAb did not prevent disease, indicating that CD40/CD40L costimulation is not required for diabetes in IL-10-NOD mice. Immunization of IL-10-NOD mice with CFA or heat-shock protein 65, known to block diabetes in NOD mice, had no effect on their diabetes. We demonstrate that IL-10 contributes early to the pathology of diabetes via a CD8+ T cell pathway, eliminating the requirement for B lymphocytes and CD40-CD40L costimulation. Our findings provide a mechanism for the participation of IL-10 in the early development of diabetes.
白细胞介素-10（IL-10）对于非肥胖糖尿病（NOD）小鼠糖尿病早期阶段至关重要，但后期对其发展具有保护作用。IL-10在这些小鼠中介导糖尿病发生途径的机制尚不清楚。在此，我们剖析了胰岛中表达IL-10的转基因（tg）NOD小鼠（IL-10-NOD小鼠）发生糖尿病的细胞和共刺激需求。我们发现单独的IL-10不会导致糖尿病，因为IL-10-NOD小鼠与NOD-scid小鼠回交产生的后代（IL-10-NOD-scid小鼠）没有糖尿病。此外，这些IL-10-NOD-scid小鼠没有淋巴细胞浸润。用耗竭性抗CD4单克隆抗体或对照单克隆抗体处理IL-10-NOD小鼠对糖尿病没有影响。令人惊讶的是，用相应单克隆抗体处理耗尽CD8⁺T细胞可抑制糖尿病，而不会减轻胰岛炎，这表明CD8⁺T细胞在疾病过程中起关键作用。有趣的是，B细胞缺陷的IL-10-NOD小鼠很容易发生糖尿病，其动力学和发病率与野生型小鼠相似，这表明疾病过程中不需要B淋巴细胞作为抗原呈递细胞。给予抗CD40配体（CD40L）单克隆抗体并不能预防疾病，这表明IL-10-NOD小鼠发生糖尿病不需要CD40/CD40L共刺激。用已知可阻断NOD小鼠糖尿病的弗氏完全佐剂（CFA）或热休克蛋白65免疫IL-10-NOD小鼠对其糖尿病没有影响。我们证明IL-10通过CD8⁺T细胞途径在糖尿病早期病理过程中起作用，消除了对B淋巴细胞和CD40-CD40L共刺激的需求。我们的发现为IL-10参与糖尿病早期发展提供了一种机制。
