CRITICAL ROLE FOR THE VAL/GLY86 HLA-DR-BETA DIMORPHISM IN AUTOANTIGEN PRESENTATION TO HUMAN T-CELLS
CRITICAL ROLE FOR THE VAL/GLY86 HLA-DR-BETA DIMORPHISM IN AUTOANTIGEN PRESENTATION TO HUMAN T-CELLS
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DOI：
10.1073/pnas.88.16.7343
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发表时间：
1991-08-01
影响因子：
11.1
通讯作者：
NEWSOMDAVIS, J
中科院分区：
文献类型：
--
作者：
ONG, B;WILLCOX, N;NEWSOMDAVIS, J
辅助T淋巴细胞识别主要组织相容性复合体11类分子的肽结合裂缝中的外来（或自身）抗原片段;它们的激活是诱导许多免疫和自身免疫应答的关键步骤。在研究后者时，我们从重症肌无力患者的胸腺中培养了一种T细胞系，以对抗这种自身免疫性疾病的靶点--人乙酰胆碱受体的重组α亚单位。该线响应于人类序列的144-156区域，而不是电鱼同源物的相同区域，其仅相差三个残基。这些CD 4 + T细胞仅在HLA-DR 4 II类分子的背景下识别该表位，其中绝对需要具有Gly 86的变体。因此，天然存在的替代物Dw14.2（Gly 86）和Dw14.1（Val 86）-其仅在整个抗原结合区中的这一个位置处不同-在呈递活性方面显示全或无差异。在位置86处的这种二态性是广泛的，发生在DR 1、DR 2、DR 3、DR 5和DR 6等位基因以及DR 4的亚型中。由于在位置70-74处具有取代的其他DR 4亚型也不能呈递该肽，并且甘氨酸残基可以是独特的灵活的，我们建议在位置86处的这种取代通过改变肽结合裂缝的构象而局部地或在一定距离处起作用。我们在这里报告的T细胞识别的这种深刻的功能后果可以解释这个保守的主要组织相容性复合体多样性的例子。
Helper T lymphocytes recognize fragments of foreign (or self) antigens in the peptide-binding clefts of major histocompatibility complex class 11 molecules; their activation is a crucial step in the induction of many immune and autoimmune responses. While studying the latter, we raised a T-cell line from the thymus of a myasthenia gravis patient against recombinant alpha-subunit of the human acetylcholine receptor, the target of this autoimmune disease. The line responds to the 144-156 region of the human sequence and not to the same region of the electric fish homolog, which differs by only three residues. These CD4+ T cells recognize this epitope only in the context of HLA-DR4 class II molecules, of which the variants with Gly86 are absolutely required. Thus the naturally occurring alternatives Dw14.2 (Gly86) and Dw14.1 (Val86) - which differ only at this one position in the entire antigen-binding region - show an all-or-nothing difference in presenting activity. This dimorphism at position 86 is widespread, occurring in subtypes of DR1, DR2, DR3, DR5, and DR6 alleles as well as DR4. Since other DR4 subtypes with substitutions at positions 70-74 also fail to present this peptide, and glycine residues can be uniquely flexible, we suggest that this replacement at position 86 acts locally or at a distance by altering the conformation of the peptide-binding cleft. Such profound functional consequences for T-cell recognition as we report here may explain this example of conserved major histocompatibility complex diversity.