McMenamin C, Holt P G
Western Australian Research Institute for Child Health, Princess Margaret Hospital, Perth.
J Exp Med. 1993 Sep 1;178(3):889-99. doi: 10.1084/jem.178.3.889.
The immunological basis for atopy is currently ascribed to an inherent bias in the CD4+ T cell response to nonreplicating antigens presented at mucosal surfaces, resulting in dominance of the T helper 2 (Th2) interleukin 4 (IL-4)-producing phenotype, which favors IgE production. In contrast, the "normal" response to such antigens involves a predominance of interferon gamma (IFN-gamma)-producing Th1 clones. This difference has been suggested to be the result of active selection in atopics for Th2 (and hence against Th1) clones at the time of initial antigen presentation. In the study below, we demonstrate that the natural immune response to inhaled protein antigens, particularly in animals expressing the low immunoglobulin E (IgE) responder phenotype, includes a major histocompatibility complex (MHC) class I-restricted CD8+ T cell component, the appearance of which is associated with active suppression of IgE antibody production. Thus, continued exposure of rats to aerosolized ovalbumin (OVA) antigen elicits a transient IgE response, that is terminated by the onset of a state of apparent "tolerance" to further challenge, and this tolerant state is transferable to naive animals with CD8+ T cells. Kinetic studies on in vitro T cell reactivity in these aerosol-exposed rats demonstrated biphasic CD4+ Th2 responses which terminated, together with IgE antibody production, and coincident with the appearance of MHC class I-restricted OVA-specific IFN-gamma-producing CD8+ T cells. However, the latter were not autonomous in vitro and required a source of exogenous IL-2 for initial activation, which in CD(8+)-enriched splenocyte cultures could be provided by small numbers of contaminating OVA-specific CD4+ T cells. This represents the first formal evidence for the induction of an MHC class I-restricted T cell response to natural mucosal exposure to an inert protein antigen, and is consistent with a growing literature demonstrating sensitization of MHC class I-restricted CD8+ T cells by deliberate immunization with soluble proteins. We suggest that crossregulation of MHC class II-restricted CD4+ T cells via cytokine signals generated in parallel CD8+ T cell responses represents a covert and potentially important selection pressure that can shape the nature of host responses to nonreplicating antigens presented at mucosal surfaces.
特应性的免疫基础目前被归因于CD4 + T细胞对黏膜表面呈递的非复制性抗原反应中固有的偏向性，导致产生白细胞介素4（IL - 4）的辅助性T细胞2（Th2）表型占主导，这有利于IgE的产生。相比之下，对这类抗原的“正常”反应涉及产生干扰素γ（IFN - γ）的Th1克隆占优势。有人认为这种差异是由于在初次抗原呈递时特应性个体对Th2克隆（因此对Th1克隆不利）进行了积极选择。在下面的研究中，我们证明对吸入性蛋白质抗原的天然免疫反应，特别是在表达低免疫球蛋白E（IgE）反应表型的动物中，包括主要组织相容性复合体（MHC）I类限制性CD8 + T细胞成分，其出现与IgE抗体产生的主动抑制相关。因此，持续将大鼠暴露于雾化的卵清蛋白（OVA）抗原会引发短暂的IgE反应，该反应会因对进一步刺激出现明显的“耐受”状态而终止，并且这种耐受状态可通过CD8 + T细胞转移至未接触过抗原的动物。对这些经气溶胶暴露的大鼠体外T细胞反应性的动力学研究表明，CD4 + Th2反应呈双相性，与IgE抗体产生一起终止，并与MHC I类限制性OVA特异性产生IFN - γ的CD8 + T细胞的出现同时发生。然而，后者在体外并非自主反应，初始激活需要外源性IL - 2来源，在富含CD8 +的脾细胞培养物中，少量污染的OVA特异性CD4 + T细胞可提供这种外源性IL - 2。这是首次正式证明对天然黏膜暴露于惰性蛋白质抗原诱导了MHC I类限制性T细胞反应，并且与越来越多的文献一致，这些文献表明通过用可溶性蛋白质进行刻意免疫可使MHC I类限制性CD8 + T细胞致敏。我们认为，通过平行的CD8 + T细胞反应产生的细胞因子信号对MHC II类限制性CD4 + T细胞进行交叉调节，代表了一种隐蔽且可能重要的选择压力，它可以塑造宿主对黏膜表面呈递的非复制性抗原的反应性质。
