Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells.
Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells.
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DOI：
10.1084/jem.20110640
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发表时间：
2011-12-19
期刊：
影响因子：
--
通讯作者：
Unanue ER
中科院分区：
文献类型：
--
作者：
Ireland JM;Unanue ER
DC和巨噬细胞的瓜氨酸肽呈递是组成性的，而B细胞仅在血清饥饿或BCR连接诱导的自噬下呈递修饰的肽。对瓜氨酸化自身蛋白的抗体反应见于自身免疫，特别是在类风湿性关节炎中，它们可作为诊断指标。我们在这里表明，蛋白质鸡蛋清溶菌酶（HEL）的加工导致瓜氨酸肽的抗原呈递细胞提出的II类MHC分子。瓜氨酸化肽的呈递而非未修饰肽的呈递与自噬相关。树突状细胞（DC）、巨噬细胞和胸腺DC组成型呈递瓜氨酸肽。他们的治疗与3-甲基腺嘌呤（3 MA）阻断介绍瓜氨酸化HEL肽，但介绍未修饰的肽不受影响。在正常培养条件下，在B细胞或B淋巴瘤细胞上未检测到瓜氨酸化肽的呈递。在B细胞中，瓜氨酸化肽的呈递需要B细胞抗原受体的参与，这也受到3 MA的抑制。表达B淋巴瘤的HEL细胞仅在短暂的血清饥饿后呈现瓜氨酸肽。这种呈递通过3 MA或通过Atg 5表达的减少而减少。未修饰的肽的呈现没有改变。研究结果表明，通过产生这种新表位，自噬和自身反应性之间存在联系。
Citrullinated peptide presentation by DCs and macrophages is constitutive, whereas B cells present modified peptides only with autophagy induced by serum starvation or BCR ligation. Antibody responses to citrullinated self-proteins are found in autoimmunities, particularly in rheumatoid arthritis, where they serve as a diagnostic indicator. We show here that processing of the protein hen egg-white lysozyme (HEL) resulted in citrullination of peptides presented on class II MHC molecules by antigen-presenting cells. The presentation of the citrullinated peptides but not of the unmodified peptides was associated with autophagy. Dendritic cells (DCs), macrophages, and thymic DCs presented citrullinated peptides constitutively. Their treatment with 3-methyladenine (3MA) blocked presentation of citrullinated HEL peptides, but presentation of unmodified peptides was not affected. Presentation of citrullinated peptides was not detected on B cells or B lymphoma cells under normal culture conditions. In B cells, engagement of the B cell antigen receptor was required for presentation of the citrullinated peptides, also inhibited by 3MA. B lymphoma–expressing HEL cells presented citrullinated peptides only after brief serum starvation. This presentation was reduced by 3MA or by reduction in Atg5 expression. Presentation of the unmodified peptides was not changed. The findings indicate a linkage between autophagy and autoreactivity through the generation of this neo-epitope.
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