Retinoic acid receptor-related orphan receptor a regulates bystander activation of memory CD8+ T cells

Background: Memory CD8+ T cells sense inflammation and rapidly produce interferon-? (IFN-?) 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 a (RORa) belongs to the nuclear receptor family and regulates gene transcription in ligand-dependent manner. Although RORa is highly expressed in memory CD8+ T cells, its functional relevance has not been investigated. Methods: Primary and secondary memory T cells that are sufficient or deficient of RORa were induced by adoptive transfer of naïve OT-I T cells to recipient mice and subsequent infection with Listeria monocytogenes expressing ovalbumin (LM-OVA). RORa expression in memory T cells were examined by quantitative PCR. The target genes of RORa in memory T cells were explored by RNA-sequencing and verified by RORa overexpression in postactivated T cells. The impact of RORa-deficiency on bystander activation was assessed by stimulating memory T cells with inflammatory cytokines in vitro or injecting lipopolysaccharide (LPS) into mice bearing memory T cells. Results: RORa expression was remarkably elevated in secondary memory CD8+ T cells along with the enrichment of effector-like memory T cells. RORa primarily acted as a transcription factor in regulating the gene expression of the TL1A receptor. RORa deficiency abrogated the IFN-? production by memory CD8+ T cells in response to IL-12 + TL1A in vitro and diminished the bystander response to LPS-induced inflammation in vivo. Conclusion: 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. Overall design: ChIP-seq data of activated CD8+ T cells retrovially overexpressing Rora fused with AM tag. Cells expressing only AM tag were used as control.