RORα governs CD8+ T cell memory subset specification and offers a therapeutic node for antiviral immunity 2259080

Abstract Introduction The establishment of immunological memory is crucial for durable antiviral immunity and underlies effective vaccine design in enhancing memory responses. The retinoic acid receptor—related orphan receptor α(RORα), a ligand-regulated transcription factor of the nuclear receptor superfamily, has been implicated in CD8+ T cell immunity, yet its role remains poorly defined. Methods To investigate this, we integrated genomic approaches with both genetic and pharmacologic perturbations of RORα to examine its role in CD8+ T cell development during antiviral responses. Results RORα-deficient mice infected with acute lymphocytic choriomeningitis virus (LCMV) exhibited fewer virus-specific CD8+ T cells and higher splenic viral titers at day 5 post-infection than wild-type controls. Despite reduced numbers, RORα-deficient CD8+ T cells showed enhanced cytotoxic potential, indicating that RORα modulates effector programming rather than overall functional capacity. RORα deficiency also led to increased migration and redistribution of CD8+ T cells into non-lymphoid compartments, particularly the liver and adipose tissues, and promoted the development of memory precursors (MP), peripheral memory (TPM), and tissue-resident memory (TRM) populations. Single-cell RNA-seq and ATAC-seq revealed enrichment of transcriptional and chromatin programs linked to MP and TRM gene signatures, including elevated expression of Tcf7 and Runx family members, alongside reduced accessibility at loci governing terminal effector differentiation. Pharmacologic inhibition of RORα with the RORα-selective inverse agonist, SR3335, recapitulated the knockout phenotype, favoring memory CD8+ T cell differentiation over terminal effectors. Conclusion Collectively, our data reveal distinct programming of CD8 T effector versus memory populations attributable to RORα activity. As a ligand-regulated transcription factor, RORα may be a promising target to enhance CD8+ T cell memory responses for improved vaccines and cell-based immunotherapies. Funding Source N/A Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)