美国康奈尔大学J. Magarian Blander研究组发现，树突状细胞中的TAP功能障碍可启动非经典的交叉呈递来活化T细胞。该项研究成果于2021年3月31日在线发表在《自然—免疫学》杂志上。

据研究人员介绍，经典的主要组织相容性复合体I类（MHC-1）呈递依赖于与抗原加工相关的转运蛋白（TAP）将胞质多肽送入内质网（ER）。病毒使TAP失去了阻断MHC-1呈递的能力，并逃避了具有细胞毒性的CD8⁺T细胞。抵抗病毒的CD8⁺T细胞活化被认为仅依赖于未感染的TAP树突状细胞的交叉呈递。

研究人员发现，即使在所有造血细胞中都不存在TAP的情况下，在病毒感染期间也可以动员保护性CD8⁺T细胞。TAP阻滞耗尽了MHC-1分子的内体循环，因此削弱了Toll样受体调节的交叉呈递。相反，MHC-1分子积聚在ER-高尔基体中隔室（ERGIC）中，与Toll样受体发生隔离，并选择ER-SNARE Sec22b介导的囊泡运输与內吞的抗原相交并拯救交叉呈递。因此，当树突状细胞中经典的MHC-1呈递和依赖于内体循环的交叉呈递受到损害时，依赖于ERGIC的MHC-1的细胞自主非经典交叉呈递会阻止TAP功能障碍，从而介导CD8⁺T细胞的活化。

附：英文原文

Title: TAP dysfunction in dendritic cells enables noncanonical cross-presentation for T cell priming

Author: Gatan Barbet, Priyanka Nair-Gupta, Michael Schotsaert, Stephen T. Yeung, Julien Moretti, Fabian Seyffer, Giorgi Metreveli, Thomas Gardner, Angela Choi, Domenico Tortorella, Robert Tamp, Kamal M. Khanna, Adolfo Garca-Sastre, J. Magarian Blander

Issue&Volume: 2021-03-31

Abstract: Classic major histocompatibility complex class I (MHC-I) presentation relies on shuttling cytosolic peptides into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). Viruses disable TAP to block MHC-I presentation and evade cytotoxic CD8+ T cells. Priming CD8+ T cells against these viruses is thought to rely solely on cross-presentation by uninfected TAP-functional dendritic cells. We found that protective CD8+ T cells could be mobilized during viral infection even when TAP was absent in all hematopoietic cells. TAP blockade depleted the endosomal recycling compartment of MHC-I molecules and, as such, impaired Toll-like receptor–regulated cross-presentation. Instead, MHC-I molecules accumulated in the ER–Golgi intermediate compartment (ERGIC), sequestered away from Toll-like receptor control, and coopted ER-SNARE Sec22b-mediated vesicular traffic to intersect with internalized antigen and rescue cross-presentation. Thus, when classic MHC-I presentation and endosomal recycling compartment–dependent cross-presentation are impaired in dendritic cells, cell-autonomous noncanonical cross-presentation relying on ERGIC-derived MHC-I counters TAP dysfunction to nevertheless mediate CD8+ T cell priming.

DOI: 10.1038/s41590-021-00903-7

Source: https://www.nature.com/articles/s41590-021-00903-7