Chen Y, Inobe J, Kuchroo V K, Baron J L, Janeway C A, Weiner H L
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):388-91. doi: 10.1073/pnas.93.1.388.
Orally administered antigens induce a state of immunologic hyporesponsiveness termed oral tolerance. Different mechanisms are involved in mediating oral tolerance depending on the dose fed. Low doses of antigen generate cytokine-secreting regulatory cells, whereas high doses induce anergy or deletion. We used mice transgenic for a T-cell receptor (TCR) derived from an encephalitogenic T-cell clone specific for the acetylated N-terminal peptide of myelin basic protein (MBP) Ac-1-11 plus I-Au to test whether a regulatory T cell could be generated from the same precursor cell as that of an encephalitogenic Th1 cell and whether the induction was dose dependent. The MBP TCR transgenic mice primarily have T cells of a precursor phenotype that produce interleukin 2 (IL-2) with little interferon gamma (IFN-gamma), IL-4, or transforming growth factor beta (TGF-beta). We fed transgenic animals a low-dose (1 mg x 5) or high-dose (25 mg x 1) regimen of mouse MBP and without further immunization spleen cells were tested for cytokine production. Low-dose feeding induced prominent secretion of IL-4, IL-10, and TGF-beta, whereas minimal secretion of these cytokines was observed with high-dose feeding. Little or no change was seen in proliferation or IL-2/IFN-gamma secretion in fed animals irrespective of the dose. To demonstrate in vivo functional activity of the cytokine-secreting cells generated by oral antigen, spleen cells from low-dose-fed animals were adoptively transferred into naive (PLJ x SJL)F1 mice that were then immunized for the development of experimental autoimmune encephalomyelitis (EAE). Marked suppression of EAE was observed when T cells were transferred from MBP-fed transgenic animals but not from animals that were not fed. In contrast to oral tolerization, s.c. immunization of transgenic animals with MBP in complete Freund's adjuvant induced IFN-gamma-secreting Th1 cells in vitro and experimental encephalomyelitis in vivo. Despite the large number of cells reactive to MBP in the transgenic animals, EAE was also suppressed by low-dose feeding of MBP prior to immunization. These results demonstrate that MBP-specific T cells can differentiate in vivo into encephalitogenic or regulatory T cells depending upon the context by which they are exposed to antigen.
口服抗原可诱导一种称为口服耐受的免疫低反应状态。根据喂食剂量的不同，介导口服耐受涉及不同的机制。低剂量抗原可产生分泌细胞因子的调节性细胞，而高剂量抗原则诱导无反应性或细胞缺失。我们使用了转染了源自针对髓鞘碱性蛋白（MBP）乙酰化N端肽Ac-1-11加I-Au的致脑炎性T细胞克隆的T细胞受体（TCR）的小鼠，以测试调节性T细胞是否可由与致脑炎性Th1细胞相同的前体细胞产生，以及诱导是否具有剂量依赖性。MBP TCR转基因小鼠主要具有前体表型的T细胞，这些T细胞产生白细胞介素2（IL-2），而几乎不产生干扰素γ（IFN-γ）、IL-4或转化生长因子β（TGF-β）。我们给转基因动物喂食低剂量（1mg×5）或高剂量（25mg×1）方案的小鼠MBP，且在不进行进一步免疫的情况下，检测脾细胞的细胞因子产生情况。低剂量喂食诱导了IL-4、IL-10和TGF-β的显著分泌，而高剂量喂食时观察到这些细胞因子的分泌极少。无论剂量如何，喂食动物的增殖或IL-2/IFN-γ分泌几乎没有变化。为了证明口服抗原产生的分泌细胞因子的细胞在体内的功能活性，将低剂量喂食动物的脾细胞过继转移到未接触过抗原的（PLJ×SJL）F1小鼠中，然后对这些小鼠进行免疫以诱发实验性自身免疫性脑脊髓炎（EAE）。当T细胞从喂食MBP的转基因动物转移时，观察到EAE受到显著抑制，而从未喂食的动物转移的T细胞则没有这种抑制作用。与口服耐受相反，用完全弗氏佐剂中的MBP对转基因动物进行皮下免疫，在体外诱导了分泌IFN-γ的Th1细胞，在体内诱发了实验性脑脊髓炎。尽管转基因动物中有大量对MBP有反应的细胞，但在免疫前低剂量喂食MBP也可抑制EAE。这些结果表明，MBP特异性T细胞可在体内根据接触抗原的环境分化为致脑炎性或调节性T细胞。
