The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase.
The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase.
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DOI：
10.1084/jem.191.4.603
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发表时间：
2000-02-21
影响因子：
15.3
通讯作者：
McAdam, S N
中科院分区：
文献类型：
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作者：
Arentz-Hansen, H;Korner, R;Molberg, O;Quarsten, H;Vader, W;Kooy, Y M;Lundin, K E;Koning, F;Roepstorff, P;Sollid, L M;McAdam, S N
由于乳糜泻（CD）而对小麦面筋蛋白不耐受的绝大多数患者是人类组织相容性白细胞抗原（HLA）-DQ 2+，其余少数正常表达HLA-DQ 8。这两种II类分子主要负责将谷蛋白肽呈递给谷蛋白特异性T细胞，所述谷蛋白特异性T细胞仅在CD患者的肠道中发现，而在对照组中未发现。有趣的是，组织转氨酶（tTG）介导的麦醇溶蛋白脱酰胺在肠道T细胞识别这种食物抗原中起着重要作用。在这里，我们使用重组抗原证明了成人CD中肠道T细胞对α-麦醇溶蛋白的反应集中在两个免疫显性的DQ 2限制性肽上，这两个肽被麦醇溶蛋白的7个残基片段重叠。我们发现，tTG将该片段内的谷氨酰胺残基转化为谷氨酸，并且该过程对T细胞识别至关重要。来自16个不同成人患者的谷蛋白特异性T细胞系都对这些脱酰胺肽中的一种或两种有反应，表明这些表位与疾病病理高度相关。结合研究表明，脱酰胺肽显示出对DQ 2的亲和力增加，DQ 2是一种已知优先结合含有带负电荷残基的肽的分子。有趣的是，对于不同的表位，修饰的谷氨酰胺被容纳在DQ 2的不同口袋中。这些结果表明，修饰的锚残基，导致改善的亲和力的主要组织相容性复合体（MHC），和改变构象的肽-MHC复合物可能是一个关键因素，导致T细胞反应麦醇溶蛋白和口服不耐受的面筋中发现的CD。
The great majority of patients that are intolerant of wheat gluten protein due to celiac disease (CD) are human histocompatibility leukocyte antigen (HLA)-DQ2+, and the remaining few normally express HLA-DQ8. These two class II molecules are chiefly responsible for the presentation of gluten peptides to the gluten-specific T cells that are found only in the gut of CD patients but not of controls. Interestingly, tissue transglutaminase (tTG)-mediated deamidation of gliadin plays an important role in recognition of this food antigen by intestinal T cells. Here we have used recombinant antigens to demonstrate that the intestinal T cell response to α-gliadin in adult CD is focused on two immunodominant, DQ2-restricted peptides that overlap by a seven-residue fragment of gliadin. We show that tTG converts a glutamine residue within this fragment into glutamic acid and that this process is critical for T cell recognition. Gluten-specific T cell lines from 16 different adult patients all responded to one or both of these deamidated peptides, indicating that these epitopes are highly relevant to disease pathology. Binding studies showed that the deamidated peptides displayed an increased affinity for DQ2, a molecule known to preferentially bind peptides containing negatively charged residues. Interestingly, the modified glutamine is accommodated in different pockets of DQ2 for the different epitopes. These results suggest modifications of anchor residues that lead to an improved affinity for major histocompatibility complex (MHC), and altered conformation of the peptide–MHC complex may be a critical factor leading to T cell responses to gliadin and the oral intolerance of gluten found in CD.