Author

Sean Campbell

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Open access Jul 2026

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

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. 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. 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. 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. N/A Immune Response Regulation: Molecular Mechanisms (IRM)

Jonathan Chuck, Sean Campbell, Anna Schell et al. · Journal of Immunology · 0 citations

Jul 2026

Mapping REV-ERBα’s Protein-Protein Interactions to Understand TH17 Cell Regulation and Inflammation 2258028

TH17 cells are a subset of CD4+ T cells that mediate autoimmune and chronic inflammatory pathology. Our lab has previously demonstrated that REV-ERBα, a member of the nuclear receptor superfamily of ligand-regulated transcription factors, represses TH17 development in vitro and protects against relevant models of disease in vivo. While REV-ERBα’s target genes and binding sites have been identified across multiple tissues, little is known about the transcriptional machinery that drives its function. We coupled MiniTurboID proximity labeling with label-free proteomics to 1) identify key proteins that facilitate REV-ERBα-mediated gene repression in primary, murine TH17 cells and 2) further understand how ligands modulate this process. Furthermore, we have conducted a pooled in vivo RNAi screen to examine our proteomics hits in a physiologically relevant context. Specifically, we utilized Il17a reporter REV-ERB deficient and sufficient T-cells along with shRNAs targeting our identified REV-ERBα interactors in a mouse model of colitis. Comparison of the REV-ERBα interactome induced by the presence and absence of endogenous ligand binding reveals potential canonical and non-canonical mechanisms of repression. Additionally, comparison of the shRNAs enriched in colon cells expressing high versus low levels of IL-17A have elucidated which REV-ERBα interactors regulate TH17 pathogenicity in a REV-ERB-dependent manner. Ultimately, these efforts aim to bolster our understanding of the REV-ERBs, nuclear receptor biology, and TH17 pathogenesis–all of which may inform the development of focused therapeutics for treatment of autoimmune and chronic inflammatory diseases. NA Basic Autoimmunity (BA)

Bin-Bin Schell, S. Mosure, Timothy R. O’Leary et al. · Journal of Immunology · 0 citations