Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
J Immunol. 2010 Mar 15;184(6):2776-84. doi: 10.4049/jimmunol.0901445. Epub 2010 Feb 8.
Accumulating evidence suggests that the dichotomy between tolerance and active IgA immunity in mucosal immune responses is regulated at the APC level. Therefore, immunomodulation of the APC could be an effective mechanism to control the two response patterns. In this study, we demonstrate that ADP-ribosylation controls the outcome of tolerance or active effector T cell immunity to an internal peptide p323-339 from OVA inserted into the cholera toxin (CT)-derived CTA1-OVA-DD adjuvant. We found that a single point mutation, CTA1R7K-OVA-DD, resulting in lack of enzymatic activity, promoted peptide-specific tolerance in TCR transgenic CD4(+) T cells following a single intranasal (i.n.) treatment. The CTA1R7K-OVA-DD-induced tolerance was strong, long-lasting, and impaired the ability of adoptively transferred naive peptide-specific CD4(+) T cells to respond to Ag-challenge, irrespective if this was given i.p or i.n. The tolerance correlated with induction of regulatory T cells of the regulatory T type 1 characterized by CD25(-)Foxp3(-)CD4(+) T cells producing IL-10. In contrast, in IL-10-deficient mice, no peptide-specific tolerance was observed, and these mice exhibited unimpaired CD4(+) T cell responsiveness to recall Ag irrespective of if they were untreated (PBS) or treated i.n. with CTA1R7K-OVA-DD. Thus, for the first time, we can provide unequivocal proof that ADP-ribosylation can control the outcome of mucosal Ag exposure from tolerance to an enhanced effector CD4(+) T cell response. The exploitation of this system for clinical treatment of autoimmune diseases is discussed.
越来越多的证据表明，黏膜免疫反应中耐受和主动 IgA 免疫之间的二分法是在 APC 水平上调节的。因此，APC 的免疫调节可能是控制两种反应模式的有效机制。在这项研究中，我们证明了 ADP-ribosylation 控制了对插入霍乱毒素（CT）衍生的 CTA1-OVA-DD 佐剂中的 OVA 内部肽 p323-339 的耐受或主动效应 T 细胞免疫的结果。我们发现，单点突变 CTA1R7K-OVA-DD，导致缺乏酶活性，在单次鼻腔（i.n.）治疗后促进 TCR 转基因 CD4(+) T 细胞对肽的特异性耐受。CTA1R7K-OVA-DD 诱导的耐受是强大的、持久的，并且损害了过继转移的幼稚肽特异性 CD4(+) T 细胞对 Ag 挑战的反应能力，无论是否通过 i.p 或 i.n. 给予。这种耐受与调节性 T 细胞 1 型的调节性 T 细胞的诱导相关，其特征为 CD25(-)Foxp3(-)CD4(+) T 细胞产生 IL-10。相比之下，在 IL-10 缺陷型小鼠中，没有观察到肽特异性耐受，并且这些小鼠表现出对回忆性 Ag 的未受损的 CD4(+) T 细胞反应能力，无论它们是否未经处理（PBS）或经鼻腔（i.n.）用 CTA1R7K-OVA-DD 治疗。因此，我们首次可以提供确凿的证据证明 ADP-ribosylation 可以控制黏膜 Ag 暴露从耐受到增强的效应 CD4(+) T 细胞反应的结果。讨论了该系统在自身免疫性疾病的临床治疗中的应用。
