Endogenous antigen processing drives the primary CD4+ T cell response to influenza.
Endogenous antigen processing drives the primary CD4+ T cell response to influenza.
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DOI：
10.1038/nm.3958
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发表时间：
2015-10
期刊：
影响因子：
82.9
通讯作者：
Eisenlohr LC
中科院分区：
文献类型：
--
作者：
Miller MA;Ganesan AP;Luckashenak N;Mendonca M;Eisenlohr LC
按照惯例，CD 4 + T淋巴细胞识别来自与MHC II类分子组合的内化抗原的外源和自身肽。已经鉴定了表位产生的替代途径，但它们对宿主防御的贡献尚未确定。我们在小鼠感染模型中表明，CD 4 + T细胞对流感的反应，对持久保护免受病毒的影响至关重要，主要是由受感染的抗原呈递细胞内合成的抗原的非常规加工驱动的，而不是由内吞病毒体或受感染细胞材料的经典加工驱动的。对所涉及的细胞组分（包括H2-M分子伴侣、蛋白酶体和γ-干扰素诱导型溶酶体巯基还原酶）的研究显示，在单个表位的产生中存在相当大的异质性，这种安排确保了肽的多样性和广泛的CD 4 + T细胞参与。这些结果可以从根本上修改合理疫苗设计的策略，并可能导致对诱导自身免疫和抗肿瘤反应的关键见解。
By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with MHC class II molecules. Alternative pathways of epitope production have been identified but their contributions to host defense have not been established. We show here in a mouse infection model that the CD4+ T cell response to influenza, critical for durable protection from the virus, is driven principally by unconventional processing of antigen synthesized within the infected antigen-presenting cell, not by classical processing of endocytosed virions or material from infected cells. Investigation of the cellular components involved, including the H2-M molecular chaperone, the proteasome, and gamma-interferon inducible lysosomal thiol reductase revealed considerable heterogeneity in the generation of individual epitopes, an arrangement that ensures peptide diversity and broad CD4+ T cell engagement. These results could fundamentally revise strategies for rational vaccine design and may lead to key insights into the induction of autoimmune and anti-tumor responses.