title: Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration.
abstract: Dendritic cells (DCs) are the primary leukocytes responsible for priming T cells. To find and activate naïve T cells, DCs must migrate to lymph nodes, yet the cellular programs responsible for this key step remain unclear. DC migration to lymph nodes and the subsequent T-cell response are disrupted in a mouse we recently described lacking the NOD-like receptor NLRP10 (NLR family, pyrin domain containing 10); however, the mechanism by which this pattern recognition receptor governs DC migration remained unknown. Using a proteomic approach, we discovered that DCs from Nlrp10 knockout mice lack the guanine nucleotide exchange factor DOCK8 (dedicator of cytokinesis 8), which regulates cytoskeleton dynamics in multiple leukocyte populations; in humans, loss-of-function mutations in Dock8 result in severe immunodeficiency. Surprisingly, Nlrp10 knockout mice crossed to other backgrounds had normal DOCK8 expression. This suggested that the original Nlrp10 knockout strain harbored an unexpected mutation in Dock8, which was confirmed using whole-exome sequencing. Consistent with our original report, NLRP3 inflammasome activation remained unaltered in NLRP10-deficient DCs even after restoring DOCK8 function; however, these DCs recovered the ability to migrate. Isolated loss of DOCK8 via targeted deletion confirmed its absolute requirement for DC migration. Because mutations in Dock genes have been discovered in other mouse lines, we analyzed the diversity of Dock8 across different murine strains and found that C3H/HeJ mice also harbor a Dock8 mutation that partially impairs DC migration. We conclude that DOCK8 is an important regulator of DC migration during an immune response and is prone to mutations that disrupt its crucial function.
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Jayendra Kumar
authors.initials: JK
authors.lastname: Krishnaswamy
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Arpita
authors.initials: A
authors.lastname: Singh
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Uthaman
authors.initials: U
authors.lastname: Gowthaman
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Renee
authors.initials: R
authors.lastname: Wu
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Pavane
authors.initials: P
authors.lastname: Gorrepati
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sales Nascimento
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Antonia
authors.initials: A
authors.lastname: Gallman
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Immunobiology and.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Rhebergen
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Samuele
authors.initials: S
authors.lastname: Calabro
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ranney
authors.affiliation: Computational Sciences, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Anuj
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755;
authors.forename: Matthew
authors.initials: M
authors.lastname: Ranson
authors.affiliation: Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755;
authors.forename: James D
authors.initials: JD
authors.lastname: Gorham
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Zachary
authors.initials: Z
authors.lastname: McCaw
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Steven R
authors.initials: SR
authors.lastname: Kleeberger
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria;
authors.forename: Leonhard X
authors.initials: LX
authors.lastname: Heinz
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria;
authors.forename: André C
authors.initials: AC
authors.lastname: Müller
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria;
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria;
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Institute for Immunology, Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Jorge
authors.initials: J
authors.lastname: Henao-Mejia
authors.affiliation: Inflammation Program, Department of Internal Medicine, University of Iowa, Iowa City, IA 52241; and.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06032.
authors.forename: Adam
authors.initials: A
authors.lastname: Williams
authors.affiliation: Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520; stephanie.eisenbarth@yale.edu richard.flavell@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Departments of Laboratory Medicine and Immunobiology and stephanie.eisenbarth@yale.edu richard.flavell@yale.edu.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D017354:Point Mutation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C494352:NLRP10 protein, human
keywords: C3H/HeJ; CDC42; DOCK8; NLRP10; dendritic cell