title: DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice.
abstract: In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA(+)CCR7(-) phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells.
authors: Department of Immunology, The John Curtin School of Medical Research , Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors: Katrina L
authors: KL
authors: Randall
authors: Stephanie S-Y
authors: SS
authors: Chan
authors: Cindy S
authors: CS
authors: Ma
authors: Ivan
authors: I
authors: Fung
authors: Yan
authors: Y
authors: Mei
authors: Mehmet
authors: M
authors: Yabas
authors: Andy
authors: A
authors: Tan
authors: Peter D
authors: PD
authors: Arkwright
authors: Wafaa
authors: W
authors: Al Suwairi
authors: Saul Oswaldo
authors: SO
authors: Lugo Reyes
authors: Marco A
authors: MA
authors: Yamazaki-Nakashimada
authors: Maria de la Luz
authors: Mde L
authors: Garcia-Cruz
authors: Joanne M
authors: JM
authors: Smart
authors: Capucine
authors: C
authors: Picard
authors: Satoshi
authors: S
authors: Okada
authors: Emmanuelle
authors: E
authors: Jouanguy
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Teresa
authors: T
authors: Lambe
authors: Richard J
authors: RJ
authors: Cornall
authors: Sarah
authors: S
authors: Russell
authors: Jane
authors: J
authors: Oliaro
authors: Stuart G
authors: SG
authors: Tangye
authors: Edward M
authors: EM
authors: Bertram
authors: Christopher C
authors: CC
authors: Goodnow
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D054992:Immunological Synapses / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009975:Orthomyxoviridae / Q000502:physiology; D010641:Phenotype; D018183:Transplantation Chimera
chemical_list: C516591:DOCK8 protein, human; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D016169:Lymphocyte Function-Associated Antigen-1