Vaccines composed of mRNA and lipid nanoparticles (LNPs) activate B cells and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, T cell activation requires antigen processing and presentation by MHC molecules on specialized antigen-presenting cells (APCs). In response to viral infections, tumours, and protein- and cDNA-based vaccines, antigen presentation to CD8 T cells is particularly dependent on type 1 conventional dendritic (cDC1) cells, which are specialized for efficient cross-presentation of exogenous antigens+1,2,3,4. However, whether similar mechanisms have a role in mRNA–LNP vaccination is unclear. Here we report that mRNA–LNP vaccines do not require cDC1 cells or the WDFY4-dependent cross-presentation pathway for CD8 T cell priming but instead engage both cDC1 and cDC2 cells redundantly. While CD8 T cells primed exclusively by either cDC1 or cDC2 cells showed phenotypic differences, both could mediate anti-tumour responses and memory formation. Importantly, acquisition by cDCs of peptide–MHC-I complexes from non-haematopoietic cells, called cross-dressing, provides a substantial component of CD8 T cell priming, in a manner dependent on type I interferon. mRNA–LNP induction of cross-dressing might explain their ability to activate CD8 T cells against antigens not encoded by the vaccine.
由mRNA和脂质纳米颗粒（LNP）组成的疫苗通过诱导体内产生特定蛋白抗原来激活B细胞和T细胞。B细胞可直接被抗原激活，而T细胞的激活则需要抗原提呈细胞（APC）上的MHC分子对抗原进行加工和提呈。针对病毒感染、肿瘤以及基于蛋白质和cDNA的疫苗时，向CD8 T细胞的抗原提呈尤其依赖于1型常规树突状细胞（cDC1），这类细胞专门用于高效交叉提呈外源性抗原。然而，在mRNA-LNP疫苗接种中是否存在类似机制尚不清楚。本研究发现，mRNA-LNP疫苗不依赖cDC1细胞或WDFY4依赖的交叉提呈通路来启动CD8 T细胞，而是冗余性地同时利用cDC1和cDC2细胞。尽管仅由cDC1或cDC2启动的CD8 T细胞存在表型差异，但两者均能介导抗肿瘤免疫应答并形成记忆。重要的是，cDC通过一种依赖于I型干扰素的方式，从非造血细胞获得肽-MHC-I复合物（即交叉装扮），构成了CD8 T细胞启动的重要部分。mRNA-LNP诱导的交叉装扮可能解释了其为何能激活针对非疫苗编码抗原的CD8 T细胞。
mRNA vaccines engage unconventional pathways in CD8 T cell priming+
肿瘤(癌症)患者之家