Miyamoto Katsuichi, Kingsley Cherry I, Zhang Xingmin, Jabs Claudia, Izikson Leonid, Sobel Raymond A, Weiner Howard L, Kuchroo Vijay K, Sharpe Arlene H
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2005 Dec 1;175(11):7341-7. doi: 10.4049/jimmunol.175.11.7341.
The ICOS molecule stimulates production of the immunoregulatory cytokine IL-10, suggesting an important role for ICOS in controlling IL-10-producing regulatory T cells and peripheral T cell tolerance. In this study we investigate whether ICOS is required for development of oral, nasal, and high dose i.v. tolerance. Oral administration of encephalitogenic myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide to ICOS-deficient (ICOS-/-) mice did not inhibit experimental autoimmune encephalomyelitis (EAE), T cell proliferation, or IFN-gamma production, in striking contrast to wild-type mice. Similarly, intranasal administration of MOG(35-55) before EAE induction suppressed EAE and T cell responses in wild-type, but not in ICOS-/-, mice. In contrast, ICOS-/- mice were as susceptible as wild-type mice to high dose tolerance. These results indicate that ICOS plays an essential and specific role in mucosal tolerance and that distinct costimulatory pathways differentially regulate different forms of peripheral tolerance. Surprisingly, CD4+ cells from MOG-fed wild-type and ICOS-/- mice could transfer suppression to wild-type recipients, indicating that functional regulatory CD4+ cells can develop in the absence of ICOS. However, CD4+ T cells from MOG-fed wild-type mice could not transfer suppression to ICOS-/- recipients, suggesting that ICOS may have a key role in controlling the effector functions of regulatory T cells. These results suggest that stimulating ICOS may provide an effective therapeutic approach for promoting mucosal tolerance.
诱导共刺激分子（ICOS）可刺激免疫调节性细胞因子白细胞介素-10（IL-10）的产生，提示ICOS在调控产生IL-10的调节性T细胞及外周T细胞耐受性方面发挥重要作用。在本研究中，我们探究了ICOS对于口服、鼻腔及高剂量静脉注射耐受性的形成是否必要。给ICOS缺陷（ICOS-/-）小鼠口服致脑炎性髓鞘少突胶质细胞糖蛋白（MOG）35-55肽，并不会抑制实验性自身免疫性脑脊髓炎（EAE）、T细胞增殖或γ干扰素的产生，这与野生型小鼠形成鲜明对比。同样，在诱导EAE之前给野生型小鼠鼻腔内注射MOG(35-55)可抑制EAE及T细胞反应，但在ICOS-/-小鼠中却无此效果。相比之下，ICOS-/-小鼠与野生型小鼠对高剂量耐受性同样敏感。这些结果表明，ICOS在黏膜耐受性中发挥着至关重要且特定的作用，不同的共刺激途径以不同方式调节外周耐受性的不同形式。令人惊讶的是，喂食MOG的野生型和ICOS-/-小鼠的CD4+细胞均可将抑制作用传递给野生型受体，这表明功能性调节性CD4+细胞可在无ICOS的情况下发育。然而，喂食MOG的野生型小鼠的CD4+ T细胞无法将抑制作用传递给ICOS-/-受体，这表明ICOS可能在控制调节性T细胞的效应功能方面发挥关键作用。这些结果提示，刺激ICOS可能为促进黏膜耐受性提供一种有效的治疗方法。
