Kafle Samita, Montoya Brian, Tang Lingjuan, Tam Ying K, Muramatsu Hiromi, Pardi Norbert, Sigal Luis J
Department of Microbiology and Immunology, Bluemle Life Science Building, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada.
Mol Ther Nucleic Acids. 2024 Jul 20;35(3):102279. doi: 10.1016/j.omtn.2024.102279. eCollection 2024 Sep 10.
The role of CD4 T cells in the induction of protective CD8 T cells by mRNA lipid nanoparticle (LNP) vaccines is unknown. We used B6 or mice depleted or not of CD4 T cells and LNP vaccines loaded with mRNAs encoding the ectromelia virus (ECTV) MHC class I H-2 K-restricted immunodominant CD8 T cell epitope TSYKFESV (TSYKFESV mRNA-LNPs) or the ECTV EVM158 protein, which contains TSYKFESV (EVM-158 mRNA-LNPs). Following prime and boost with 10 μg of either vaccine, K-TSYKFESV-specific CD8 T cells fully protected male and female mice from ECTV at 29 (both mRNA-LNPs) or 90 days (EVM158 mRNA-LNPs) post boost (dpb) independently of CD4 T cells. However, at 29 dpb with 1 μg mRNA-LNPs, males had lower frequencies of K-TSYKFESV-specific CD8 T cells and were much less well protected than females from ECTV, also independently of CD4 T cells. At 90 dpb with 1 μg EVM158 mRNA-LNPs, the frequencies of K-TSYKFESV-specific CD8 T cells in males and females were similar, and both were similarly partially protected from ECTV, independently of CD4 T cells. Therefore, at optimal or suboptimal doses of mRNA-LNP vaccines, CD4 T cell help is unnecessary to induce protective anti-poxvirus CD8 T cells specific to a dominant epitope. At suboptimal doses, protection of males requires more time to develop.
CD4 T细胞在mRNA脂质纳米颗粒（LNP）疫苗诱导保护性CD8 T细胞过程中的作用尚不清楚。我们使用了CD4 T细胞已耗尽或未耗尽的B6或 小鼠，以及负载编码埃可病毒（ECTV）MHC I类H-2 K限制性免疫显性CD8 T细胞表位TSYKFESV的mRNA的LNP疫苗（TSYKFESV mRNA-LNPs）或含有TSYKFESV的ECTV EVM158蛋白（EVM-158 mRNA-LNPs）。用10μg上述任一种疫苗进行初次免疫和加强免疫后，K-TSYKFESV特异性CD8 T细胞在加强免疫后29天（两种mRNA-LNPs）或90天（EVM158 mRNA-LNPs）时能完全保护雄性和雌性小鼠免受ECTV感染，且与CD4 T细胞无关。然而，用1μg mRNA-LNPs在29天进行加强免疫时，雄性小鼠中K-TSYKFESV特异性CD8 T细胞的频率较低，且与雌性小鼠相比，其免受ECTV感染的保护作用要弱得多，这同样与CD4 T细胞无关。用1μg EVM158 mRNA-LNPs在90天进行加强免疫时，雄性和雌性小鼠中K-TSYKFESV特异性CD8 T细胞的频率相似，且二者均同样受到部分保护而免受ECTV感染，与CD4 T细胞无关。因此，在mRNA-LNP疫苗的最佳或次优剂量下，诱导针对显性表位的保护性抗痘病毒CD8 T细胞无需CD4 T细胞的辅助。在次优剂量下，雄性小鼠的保护作用需要更长时间才能形成。
