The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues
The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues
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DOI：
10.4049/jimmunol.169.2.739
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发表时间：
2002-07-15
影响因子：
4.4
通讯作者：
Vignali, DAA
中科院分区：
文献类型：
--
作者：
Arnold, PY;La Gruta, NL;Vignali, DAA
肽以确定的周期性与MHC II类分子结合，使得位于核心结合序列（P1-P9）外部的肽侧翼残基（PFR）P-1和P11暴露于溶剂中并可接近TCR。使用一种新的MHC 11类：肽结合试验，我们定义了9个免疫原性表位的结合寄存器，正式确定侧翼残基。发现受H-2A（k）、H-2A（g7）或H-2 E（k）限制的9个表位中的7个产生完全依赖于P-1或P11的T细胞，其中P-1的依赖性优于P11。这种PFR依赖性似乎受到暴露的氨基酸类型的影响，因为可以形成盐桥或氢键的残基优于小的或疏水的残基。在P-1或P11处含有丙氨酸取代以代替介导依赖性的PFR的肽的免疫原性要低得多，并且介导对天然蛋白质的体外回忆反应大幅降低，这意味着PFR识别增加了免疫原性。我们的数据表明，PFR识别是所有MHC II类限制性T细胞反应的共同事件特征。这一关键特征，这是不共享的MHC I类限制性反应，可能是基础的广泛的功能多样性显示的MHC II类限制性T细胞。
Peptides bind to MHC class II molecules with a defined periodicity such that the peptide-flanking residues (PFRs) P-1 and P11, which lie outside the core binding sequence (P1-P9), are solvent exposed and accessible to the TCR. Using a novel MHC class 11:peptide binding assay, we defined the binding register for nine immunogenic epitopes to formally identify the flanking residues. Seven of the nine epitopes, restricted by H-2A(k), H-2A(g7), or H-2E(k), were found to generate T cells that were completely dependent on either-P-1 or P11, with dependency on P-1 favored over P11. Such PFR dependency appears to be influenced by the type of amino acid exposed, in that residues that can form salt bridges or hydrogen bonds are favored over small or hydrophobic residues. Peptides containing alanine substitutions at P-1 or P11 in place of PFRs that mediate dependency were considerably less immunogenic and mediated a substantially reduced in vitro recall response to the native protein, inferring that PFR recognition increases immunogenicity. Our data suggest that PFR recognition is a common event characteristic of all MHC class II-restricted T cell responses. This key feature, which is not shared by MHC class I-restricted responses, may underlie the broad functional diversity displayed by MHC class II-restricted T cells.