Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are Selectively Recognized by CD4+ T Cells in Patients With Type 1 Diabetes
Modifying Enzymes Are Elicited by ER Stress, Generating Epitopes That Are Selectively Recognized by CD4+ T Cells in Patients With Type 1 Diabetes
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DOI：
10.2337/db17-1166
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发表时间：
2018-07-01
期刊：
影响因子：
7.7
通讯作者：
James, Eddie A.
中科院分区：
文献类型：
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作者：
Marre, Meghan L.;McGinty, John W.;James, Eddie A.
尽管有耐受机制，一些人还是会产生T细胞介导的自身免疫。翻译后修饰增加了表位呈递和/或识别的亲和力，是规避自我耐受机制的一种手段。我们研究了1型糖尿病患者对与修饰细胞抗原相对应的多肽的T细胞识别。修饰后的多肽可通过自身反应性T细胞克隆促进增殖。胰岛素瘤细胞内质网应激可使细胞内钙离子和组织转谷氨酰胺酶2(TTG2)活性升高。此外，应激状态下的人胰岛和胰岛素瘤可诱发T细胞对修饰多肽的特异性效应反应，这表明内质网应激衍生的tTG2活性产生了自身反应性T细胞识别的去氨基化新表位。1型糖尿病患者外周血中有大量针对这些表位的T细胞。具有这些特性的T细胞也从确诊为糖尿病的身体捐赠者的胰腺引流淋巴结中分离出来。综上所述，这些结果表明，在内质网应激过程中，自身抗原在细胞内被酶促修饰，产生修饰的表位，可用于启动自身免疫或进一步扩大抗原库，激活潜在的致病CD4(+)T细胞，这些细胞可能无法通过负选择有效地消除。
In spite of tolerance mechanisms, some individuals develop T-cell-mediated autoimmunity. Posttranslational modifications that increase the affinity of epitope presentation and/or recognition represent one means through which self-tolerance mechanisms can be circumvented. We investigated T-cell recognition of peptides that correspond to modified -cell antigens in subjects with type 1 diabetes. Modified peptides elicited enhanced proliferation by autoreactive T-cell clones. Endoplasmic reticulum (ER) stress in insulinoma cells increased cytosolic calcium and the activity of tissue transglutaminase 2 (tTG2). Furthermore, stressed human islets and insulinomas elicited effector responses from T cells specific for modified peptides, suggesting that ER stress-derived tTG2 activity generated deamidated neoepitopes that autoreactive T cells recognized. Patients with type 1 diabetes had large numbers of T cells specific for these epitopes in their peripheral blood. T cells with these specificities were also isolated from the pancreatic draining lymph nodes of cadaveric donors with established diabetes. Together, these results suggest that self-antigens are enzymatically modified in -cells during ER stress, giving rise to modified epitopes that could serve to initiate autoimmunity or to further broaden the antigenic repertoire, activating potentially pathogenic CD4(+) T cells that may not be effectively eliminated by negative selection.