Chronic viral infection alters PD-1 locus subnuclear localization in cytotoxic CD8+ T cells

• Published in: Cell reports (Cambridge) 2024-08, Vol.43 (8), p.114547, Article 114547
• Main Authors: Sacristán, Catarina, Youngblood, Ben A., Lu, Peiyuan, Bally, Alexander P.R., Xu, Jean Xiaojin, McGary, Katelyn, Hewitt, Susannah L., Boss, Jeremy M., Skok, Jane A., Ahmed, Rafi, Dustin, Michael L.
• Format: Article
• Language: English
• Subjects: Animals; Blimp-1; CD8+ T cell; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Nucleus - metabolism; Chronic Disease; chronic viral infection; CP: Immunology; cytotoxic; exhaustion; Genetic Loci; L-selectin; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - virology; Lymphocytic choriomeningitis virus - immunology; methylation; Mice; Mice, Inbred C57BL; PD-1; Positive Regulatory Domain I-Binding Factor 1 - genetics; Positive Regulatory Domain I-Binding Factor 1 - metabolism; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Promoter Regions, Genetic - genetics; subnuclear localization; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; transcription
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114547

During chronic infection, virus-specific CD8+ cytotoxic T lymphocytes (CTLs) progressively lose their ability to mount effective antiviral responses. This “exhaustion” is coupled to persistent upregulation of inhibitory receptor programmed death-1 (PD-1) (Pdcd1)—key in suppressing antiviral CTL responses. Here, we investigate allelic Pdcd1 subnuclear localization and transcription during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. Pdcd1 alleles dissociate from transcriptionally repressive chromatin domains (lamin B) in virus-specific exhausted CTLs but not in naive or effector CTLs. Relative to naive CTLs, nuclear positioning and Pdcd1-lamina dissociation in exhausted CTLs reflect loss of Pdcd1 promoter methylation and greater PD-1 upregulation, although a direct correlation is not observed in effector cells, 8 days post-infection. Genetic deletion of B lymphocyte-induced maturation protein 1 (Blimp-1) enhances Pdcd1-lamina dissociation in effector CTLs, suggesting that Blimp-1 contributes to maintaining Pdcd1 localization to repressive lamina. Our results identify mechanisms governing Pdcd1 subnuclear localization and the broader role of chromatin dynamics in T cell exhaustion. [Display omitted] •Pdcd1 alleles dissociate from repressive nuclear lamina in exhausted LCMV-specific CTLs•Conversely, Sell associates with repressive lamina in exhausted LCMV-specific CTLs•Loss of Pdcd1-lamina association reflects increased PD-1 expression and loss of methylation•Chronic LCMV exhaustion is coupled to increased Blimp-1 protein binding to Pdcd1 Sacristán et al. demonstrate that during mouse chronic viral infection, PD-1 alleles dissociate from transcriptionally repressive nuclear lamina in exhausted CD8+ T lymphocytes. Such allelic dissociation in exhausted cells accompanies upregulated PD-1 expression and promoter demethylation. Blimp-1 deficiency enhances Pdcd1-lamina dissociation, suggesting a mechanism for transcriptional modulation linked to chromatin dynamics.