TY - JOUR
T1 - DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice
AU - Randall, Katrina L.
AU - Chan, Stephanie S Y
AU - Ma, Cindy S.
AU - Fung, Ivan
AU - Mei, Yan
AU - Yabas, Mehmet
AU - Tan, Andy
AU - Arkwright, Peter D.
AU - Suwairi, Wafaa Al
AU - Reyes, Saul Oswaldo Lugo
AU - Yamazaki-Nakashimada, Marco A.
AU - Garcia-Cruz, Maria de la Luz
AU - Smart, Joanne M.
AU - Picard, Capucine
AU - Okada, Satoshi
AU - Jouanguy, Emmanuelle
AU - Casanova, Jean Laurent
AU - Lambe, Teresa
AU - Cornall, Richard J.
AU - Russell, Sarah
AU - Oliaro, Jane
AU - Tangye, Stuart G.
AU - Bertram, Edward M.
AU - Goodnow, Christopher C.
PY - 2011/10/24
Y1 - 2011/10/24
N2 - 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.
AB - 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.
U2 - 10.1084/jem.20110345
DO - 10.1084/jem.20110345
M3 - Article
SN - 1540-9538
SN - 0022-1007
VL - 208
SP - 2305
EP - 2320
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
ER -
