Fedoseyeva E V, Tam R C, Orr P L, Garovoy M R, Benichou G
Department of Surgery, University of California at San Francisco 94143-0508, USA.
J Exp Med. 1995 Nov 1;182(5):1481-91. doi: 10.1084/jem.182.5.1481.
Self-proteins are regularly processed for presentation to autoreactive T cells in association with both class I and class II major histocompatibility complex (MHC) molecules. The presentation of self-peptides plays a crucial role in the acquisition of T cell repertoire during thymic selection. We previously reported that the self-MHC class I peptide Ld 61-80 was immunogenic in syngeneic B10.A mice (H-2a). We showed that despite its high affinity for self-MHC class II molecules, Ld 61-80 peptide failed to induce elimination of autoreactive CD4+ T cells, presumably due to incomplete processing and presentation in the B10.A's developing thymus (cryptic-self peptide). In this report, we showed that the cryptic phenotype was not an intrinsic property of the self-peptide Ld 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2d) (dominant self-peptide). In addition, the self-peptide Ld 61-80 was found to be immunogenic in different H-2a mice while it was invariably tolerogenic in H-2d mice regardless of their background genes. We observed that Ld 61-80 bound equally well to H-2d and H-2k MHC class II molecules. Also, no correlation was found between the quantity of self-Ld protein and the tolerogenicity of Ld 61-80. Surprisingly, Ld 61-80 was not naturally presented in (H-2d x H-2a) F1 mice, indicating that the H-2a MHC locus contained a gene that impaired the presentation of the self-peptide. Analyses of T cell responses to the self-peptide in several H-2 recombinant mice revealed that the presentation of Ld 61-80 was controlled by genes that mapped to a 170-kb portion of the MHC class II region. This study shows that (a) endogenously processed self-peptides presented by MHC class II molecules are involved in shaping the CD4+ T cell repertoire in the thymus; (b) The selection of self-peptides for presentation by MHC class II molecules to nascent autoreactive T cells is influenced by nonstructural MHC genes that map to a 170-kb portion of the MHC class II region; and (c) the MHC locus of H-2a mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide Ld 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.
自身蛋白会定期被加工处理，以便与I类和II类主要组织相容性复合体（MHC）分子结合，呈递给自身反应性T细胞。自身肽的呈递在胸腺选择过程中T细胞库的形成中起着关键作用。我们之前报道过，自身MHC I类肽Ld 61 - 80在同基因的B10.A小鼠（H - 2a）中具有免疫原性。我们发现，尽管Ld 61 - 80肽对自身MHC II类分子具有高亲和力，但它未能诱导自身反应性CD4⁺ T细胞的清除，推测是由于在B10.A发育中的胸腺中加工和呈递不完全（隐蔽自身肽）。在本报告中，我们表明隐蔽表型并非自身肽Ld 61 - 80的固有特性，因为它在BALB/c小鼠（H - 2d）中是自然呈递的，随后具有耐受性（显性自身肽）。此外，发现自身肽Ld 61 - 80在不同的H - 2a小鼠中具有免疫原性，而在H - 2d小鼠中无论其背景基因如何都始终具有耐受性。我们观察到Ld 61 - 80与H - 2d和H - 2k MHC II类分子的结合能力相同。而且，未发现自身Ld蛋白的量与Ld 61 - 80的耐受性之间存在相关性。令人惊讶的是，Ld 61 - 80在（H - 2d×H - 2a）F1小鼠中并非自然呈递，这表明H - 2a MHC基因座包含一个损害自身肽呈递的基因。对几只H - 2重组小鼠中T细胞对自身肽反应的分析表明，Ld 61 - 80的呈递受映射到MHC II类区域170 kb部分的基因控制。这项研究表明：（a）由MHC II类分子呈递的内源性加工自身肽参与塑造胸腺中的CD4⁺ T细胞库；（b）MHC II类分子选择呈递给新生自身反应性T细胞的自身肽受映射到MHC II类区域170 kb部分的非结构MHC基因影响；（c）H - 2a小鼠的MHC基因座编码阻止或消除MHC II类分子呈递自身肽Ld 61 - 80的因子。这些发现可能对理解T细胞库形成和自身耐受性诱导所涉及的分子机制具有重要意义。
