title: Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection.
abstract: Endoplasmic reticulum (ER)-resident proteins are continually retrieved from the Golgi and returned to the ER by Lys-Asp-Glu-Leu (KDEL) receptors, which bind to an eponymous tetrapeptide motif at their substrate's C terminus. Mice and humans possess three paralogous KDEL receptors, but little is known about their functional redundancy, or if their mutation can be physiologically tolerated. Here, we present a recessive mouse missense allele of the prototypical mammalian KDEL receptor, KDEL ER protein retention receptor 1 (KDELR1). Kdelr1 homozygous mutants were mildly lymphopenic, as were mice with a CRISPR/Cas9-engineered frameshift allele. Lymphopenia was cell intrinsic and, in the case of T cells, was associated with reduced expression of the T-cell receptor (TCR) and increased expression of CD44, and could be partially corrected by an MHC class I-restricted TCR transgene. Antiviral immunity was also compromised, with Kdelr1 mutant mice unable to clear an otherwise self-limiting viral infection. These data reveal a nonredundant cellular function for KDELR1, upon which lymphocytes distinctly depend.
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037; Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom; Bruce.Beutler@UTSouthwestern.edu owen.siggs@gmail.com.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Siggs
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Popkin
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Philippe
authors.initials: P
authors.lastname: Krebs
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Miao
authors.initials: M
authors.lastname: Tang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Pei
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.affiliation: Medical Research Council Human Immunology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom;
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390 Bruce.Beutler@UTSouthwestern.edu owen.siggs@gmail.com.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D008231:Lymphopenia / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D018000:Receptors, Peptide / Q000235:genetics*; D014777:Virus Diseases / Q000235:genetics / Q000517:prevention & control*
chemical_list: C489304:KDELR1 protein, human; D018000:Receptors, Peptide
keywords: N-ethyl-N-nitrosourea; T-cell development; T-cell survival; lymphocytes; positive selection