The natural immune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T cell-mediated but MHC class II-restricted CD4+ T cell-dependent immune deviation resulting in selective suppression of immunoglobulin E production.
The natural immune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T cell-mediated but MHC class II-restricted CD4+ T cell-dependent immune deviation resulting in selective suppression of immunoglobulin E production.
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DOI：
10.1084/jem.178.3.889
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发表时间：
1993-09-01
期刊：
影响因子：
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通讯作者：
Holt PG
中科院分区：
文献类型：
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作者：
McMenamin C;Holt PG
目前，特应性的免疫学基础归因于 CD4+ T 细胞对粘膜表面存在的非复制抗原的反应存在固有偏差，导致 T 辅助细胞 2 (Th2) 白细胞介素 4 (IL-4) 产生表型占主导地位，有利于 IgE 产生。相反，对此类抗原的“正常”反应涉及产生干扰素γ（IFN-γ）的Th1克隆的优势。这种差异被认为是在初始抗原呈递时对 Th2（因此针对 Th1）克隆进行特应性主动选择的结果。在下面的研究中，我们证明，对吸入蛋白抗原的自然免疫反应，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有关。因此，大鼠持续暴露于雾化卵清蛋白（OVA）抗原会引发短暂的 IgE 反应，该反应通过对进一步攻击的明显“耐受”状态的开始而终止，并且这种耐受状态可转移到具有 CD8+ T 细胞的初始动物。对这些暴露于气雾剂的大鼠的体外 T 细胞反应性的动力学研究表明，双相 CD4+ Th2 反应与 IgE 抗体产生一起终止，并且与 MHC I 类限制性 OVA 特异性产生 IFN-γ 的 CD8+ T 细胞的出现一致。然而，后者在体外不是自主的，需要外源IL-2来源进行初始激活，在富含CD(8+)的脾细胞培养物中，可以由少量污染的OVA特异性CD4+T细胞提供。这代表了第一个正式证据，证明 MHC I 类限制性 T 细胞对天然粘膜暴露于惰性蛋白抗原时会产生反应，并且与越来越多的文献相一致，这些文献表明，通过使用可溶性蛋白进行有意免疫，可对 MHC I 类限制性 CD8+ T 细胞进行致敏。我们认为，通过并行 CD8+ T 细胞反应中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潜在重要的选择压力，可以塑造宿主对粘膜表面存在的非复制抗原的反应性质。
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.