Rider B J, Fraga E, Yu Q, Singh B
Department of Microbiology and Immunology, University of Western Ontario, London, Canada.
Mol Immunol. 1996 May-Jun;33(7-8):625-33. doi: 10.1016/0161-5890(96)00022-3.
Peptides eluted from murine Major Histocompatibility Complex (MHC) class II molecules are predominantly fragments of self proteins, which include apolipoprotein E, cystatin-c, transferrin receptor, MHC class II and Ii chains. These naturally processed self peptides are expected to be presented during ontogeny. Therefore, immune responses to these peptides in syngeneic hosts may be under physiological control so as to modulate auto-reactivity. As would be expected from our current understanding, T cells reactive to such antigens should be deleted or clonally anergized. To explore this possibility, we investigated the immunogenicity of a number of these self peptides in mice that express MHC class II, from which these peptides were eluted. T cell and antibody responses were measured following immunization of mice with the appropriate peptide. Surprisingly, many of these peptides were highly immunogenic in normal mice. T cells reactive to these self peptides are restricted by syngeneic MHC class II and were blocked by alpha CD4 antibodies. T cells primed with the native protein in vivo could be challenged with the appropriate self peptide in vitro. Some of the self epitopes induce Th1 cells as indicated by IFN-gamma but not IL-4 production and others induce Th2 cells. Antipeptide antibodies were detected only at higher doses of antigen. Our results suggest that T cells specific for many of the naturally processed self peptides are not deleted but tolerance to these peptides is still maintained in vivo. Presumably the high-affinity self-reactive T cells are deleted in the thymus and the low-affinity self peptide reactive T cells remain unresponsive to antigen challenge in vitro. Upon antigen priming in vivo, many of these self-reactive T cells become activated and readily respond to antigen challenge in vitro. These results point to the physiological control of the maintenance of tolerance to naturally processed self peptides.
从小鼠主要组织相容性复合体（MHC）II类分子洗脱的肽主要是自身蛋白质的片段，其中包括载脂蛋白E、胱抑素-c、转铁蛋白受体、MHC II类和Ii链。这些天然加工的自身肽预计在个体发育过程中会被呈递。因此，同基因宿主中针对这些肽的免疫反应可能处于生理控制之下，以调节自身反应性。正如我们目前的理解所预期的那样，对这类抗原具有反应性的T细胞应该被清除或克隆性失能。为了探究这种可能性，我们研究了许多从小鼠MHC II类分子中洗脱的自身肽在表达MHC II类分子的小鼠中的免疫原性。在用适当的肽免疫小鼠后，检测T细胞和抗体反应。令人惊讶的是，许多这类肽在正常小鼠中具有高度免疫原性。对这些自身肽具有反应性的T细胞受同基因MHC II类分子限制，并被α CD4抗体阻断。体内用天然蛋白质致敏的T细胞在体外可用适当的自身肽进行刺激。一些自身表位如通过IFN-γ而非IL-4的产生所表明的那样诱导Th1细胞，而其他一些则诱导Th2细胞。仅在较高剂量的抗原时才能检测到抗肽抗体。我们的结果表明，许多针对天然加工的自身肽的特异性T细胞并未被清除，但体内对这些肽的耐受性仍然得以维持。推测高亲和力的自身反应性T细胞在胸腺中被清除，而低亲和力的自身肽反应性T细胞在体外对抗原刺激仍无反应。在体内抗原致敏后，许多这类自身反应性T细胞被激活，并在体外易于对抗原刺激作出反应。这些结果表明对天然加工的自身肽耐受性维持存在生理控制。
