Rab22a controls MHC-I intracellular trafficking and antigen cross-presentation by dendritic cells
Rab22a controls MHC-I intracellular trafficking and antigen cross-presentation by dendritic cells
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DOI：
10.15252/embr.201642358
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发表时间：
2016-12-01
期刊：
影响因子：
7.7
通讯作者：
Mayorga, Luis S.
中科院分区：
文献类型：
--
作者：
Cebrian, Ignacio;Croce, Cristina;Mayorga, Luis S.
MHC-I类分子的交叉提呈使CD8(+)T淋巴细胞能够检测到外源性抗原。这一过程对启动针对许多病原体(即弓形虫)和肿瘤的细胞毒性免疫反应至关重要。为了实现高效的交叉提呈，树突状细胞(DC)具有特殊的内吞途径；然而，涉及的分子效应分子却知之甚少。在这项工作中，我们发现小GTP酶Rab22a是MHC-I运输和DC抗原交叉递呈的关键调节因子。我们的结果表明，Rab22a被募集到DC内体和吞噬体，以及含有弓形虫寄生虫的液泡中。沉默Rab22a的表达不会影响外源抗原的摄取或寄生虫的入侵，但会显著减少细胞内池和MHC-I分子的循环。Rab22a基因的敲除也阻碍了可溶性抗原、颗粒抗原和弓形虫相关抗原的交叉递呈，但不阻碍内源性MHC-I抗原通过经典的分泌途径递呈。我们的发现提供了令人信服的证据，证明Rab22a在MHC-I内吞运输中发挥核心作用，这对DC有效的交叉呈现至关重要。
Cross-presentation by MHC class I molecules allows the detection of exogenous antigens by CD8(+) T lymphocytes. This process is crucial to initiate cytotoxic immune responses against many pathogens (i.e., Toxoplasma gondii) and tumors. To achieve efficient cross-presentation, dendritic cells (DCs) have specialized endocytic pathways; however, the molecular effectors involved are poorly understood. In this work, we identify the small GTPase Rab22a as a key regulator of MHC-I trafficking and antigen cross-presentation by DCs. Our results demonstrate that Rab22a is recruited to DC endosomes and phagosomes, as well as to the vacuole containing T. gondii parasites. The silencing of Rab22a expression did not affect the uptake of exogenous antigens or parasite invasion, but it drastically reduced the intracellular pool and the recycling of MHC-I molecules. The knockdown of Rab22a also hampered the cross-presentation of soluble, particulate and T. gondii-associated antigens, but not the endogenous MHC-I antigen presentation through the classical secretory pathway. Our findings provide compelling evidence that Rab22a plays a central role in the MHC-I endocytic trafficking, which is crucial for efficient cross-presentation by DCs.