Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Sector 81, SAS Nagar Knowledge City PO Manauli, Mohali, 140306, Punjab, India.
Nat Commun. 2024 Nov 27;15(1):10300. doi: 10.1038/s41467-024-54757-2.
Age-related alterations of the immune system compromise the host's ability to respond to pathogens, but how immune aging is regulated is still poorly understood. Here, we identify via transcriptomic analysis of splenic DCs and bone marrow derived dendritic cells (BMDC) of young and aged mice, the small GTPase Rab8a as a regulator of dendritic cell (DC) functions in mice. CD11cCD11b DCs of aged in comparison to young host exhibit a diminished type I IFN response upon viral stimulation and inefficiently present exogenous antigens to CD8 T cells in vitro and in vivo. Rab8a overexpression, which is accompanied by the upregulation of Rab11, restores the functionality of these aged DCs, whereas knockdown of Rab8a reduces functionality of DCs from young mice. Mechanistically, Rab8a and Rab11 cooperate to induce efficient trafficking of peptide loaded class I MHC molecules from the ER to the cell surface. We propose that targeting Rab8a might serve as a strategy to restore DC functionality in the context of immune aging.
随着年龄的增长，免疫系统会发生改变，从而削弱宿主对病原体的反应能力，但免疫系统的衰老如何调控仍知之甚少。在这里，我们通过对年轻和老年小鼠脾脏树突状细胞（DC）和骨髓来源树突状细胞（BMDC）的转录组分析，确定小 GTPase Rab8a 是调节小鼠 DC 功能的一个关键因子。与年轻宿主相比，衰老宿主的 CD11cCD11b DC 在病毒刺激下表现出Ⅰ型干扰素反应减弱，并且在体外和体内不能有效地将外源性抗原呈递给 CD8 T 细胞。Rab8a 的过表达，伴随着 Rab11 的上调，恢复了这些衰老 DC 的功能，而 Rab8a 的敲低则降低了年轻小鼠 DC 的功能。从机制上讲，Rab8a 和 Rab11 合作诱导肽负载的 I 类 MHC 分子从内质网有效转运到细胞表面。我们提出，靶向 Rab8a 可能是恢复免疫衰老背景下 DC 功能的一种策略。
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