Cai Zimeng, Kozai Mina, Mita Hironobu, Takeuchi Hiroto, Mizuno Satoru, Matsuo Kazuhiro, Takada Kensuke
Laboratory of Molecular Medicine, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Division of Vaccinology for Clinical Development, Institute for Vaccine Research and Development, Hokkaido University (HU-IVReD), Sapporo, Japan.
Front Immunol. 2025 Aug 14;16:1647746. doi: 10.3389/fimmu.2025.1647746. eCollection 2025.
Memory CD8 T cells sense inflammation and rapidly produce interferon-γ (IFN-γ) independent of cognate antigens. This innate-like property, called bystander activation, is involved in early host defense before the antigen-specific memory response. However, the molecular mechanisms underlying this activation remain unknown. Retinoic acid receptor-related orphan receptor α (RORα) belongs to the nuclear receptor family and regulates gene transcription in ligand-dependent manner. Although RORα is highly expressed in memory CD8 T cells, its functional relevance has not been investigated.
Primary and secondary memory T cells that are sufficient or deficient of RORα were induced by adoptive transfer of naïve OT-I T cells to recipient mice and subsequent infection with expressing ovalbumin (LM-OVA). RORα expression in memory T cells was examined by quantitative PCR. The target genes of RORα in memory T cells were explored by RNA-sequencing and verified by RORα overexpression in postactivated T cells. The impact of RORα-deficiency on bystander activation was assessed by stimulating memory T cells with inflammatory cytokines or injecting lipopolysaccharide (LPS) into mice bearing memory T cells.
RORα expression was remarkably elevated in secondary memory CD8 T cells along with the enrichment of effector-like memory T cells. RORα primarily acted as a transcription factor in regulating the gene expression of the TL1A receptor. RORα deficiency abrogated the IFN-γ production by memory CD8 T cells in response to IL-12 + TL1A and diminished the bystander response to LPS-induced inflammation .
This study revealed a regulatory mechanism of bystander activation. The findings also improve our understanding of how memory T cells increase their immediate protective capacity through repeated infections and vaccinations.
记忆性CD8 T细胞可感知炎症并迅速产生γ干扰素（IFN-γ），而无需同源抗原。这种类似先天免疫的特性，即旁观者激活，参与抗原特异性记忆反应之前的早期宿主防御。然而，这种激活背后的分子机制尚不清楚。维甲酸受体相关孤儿受体α（RORα）属于核受体家族，以配体依赖的方式调节基因转录。尽管RORα在记忆性CD8 T细胞中高表达，但其功能相关性尚未得到研究。
通过将幼稚OT-I T细胞过继转移至受体小鼠并随后用表达卵清蛋白的李斯特菌（LM-OVA）感染，诱导出RORα充足或缺乏的原发性和继发性记忆T细胞。通过定量PCR检测记忆T细胞中RORα的表达。通过RNA测序探索记忆T细胞中RORα的靶基因，并通过在活化后T细胞中过表达RORα进行验证。通过用炎性细胞因子刺激记忆T细胞或向携带记忆T细胞的小鼠注射脂多糖（LPS），评估RORα缺乏对旁观者激活的影响。
随着效应样记忆T细胞的富集，继发性记忆性CD8 T细胞中RORα的表达显著升高。RORα主要作为转录因子调节TL1A受体的基因表达。RORα缺乏消除了记忆性CD8 T细胞对IL-12 + TL1A产生的IFN-γ，并减弱了对LPS诱导炎症的旁观者反应。
本研究揭示了旁观者激活的调控机制。这些发现也增进了我们对记忆T细胞如何通过反复感染和接种疫苗提高其即时保护能力的理解。
