Chronic viral infection alters PD-1 locus subnuclear localization in cytotoxic CD8+ T cells
Catarina Sacristán,
Ben A. Youngblood,
Peiyuan Lu,
Alexander P.R. Bally,
Jean Xiaojin Xu,
Katelyn McGary,
Susannah L. Hewitt,
Jeremy M. Boss,
Jane A. Skok,
Rafi Ahmed,
Michael L. Dustin
Affiliations
Catarina Sacristán
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA
Ben A. Youngblood
Emory Vaccine Center and the Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA; Immunology Department, St Jude Children’s Research Hospital, Memphis, TN, USA
Peiyuan Lu
Emory Vaccine Center and the Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
Alexander P.R. Bally
Emory Vaccine Center and the Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
Jean Xiaojin Xu
Emory Vaccine Center and the Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
Katelyn McGary
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA
Susannah L. Hewitt
Department of Pathology, New York University School of Medicine, New York, NY, USA
Jeremy M. Boss
Emory Vaccine Center and the Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
Jane A. Skok
Department of Pathology, New York University School of Medicine, New York, NY, USA
Rafi Ahmed
Emory Vaccine Center and the Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
Michael L. Dustin
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA; The Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; Corresponding author
Summary: 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.
