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DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice


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.

Type Journal
ISBN 1540-9538 (Electronic) 0022-1007 (Linking)
Authors Randall, K. L.; Chan, S. S.; Ma, C. S.; Fung, I.; Mei, Y.; Yabas, M.; Tan, A.; Arkwright, P. D.; Al Suwairi, W.; Lugo Reyes, S. O.; Yamazaki-Nakashimada, M. A.; de la Luz Garcia-Cruz, M.; Smart, J. M.; Picard, C.; Okada, S.; Jouanguy, E.; Casanova, J. L.; Lambe, T.; Cornall, R. J.; Russell, S.; Oliaro, J.; Tangye, S. G.; Bertram, E. M.; Goodnow, C. C.:
Published Date 2011-11-01
Published Volume 208
Published Issue 11
Published Pages 2305-20
Status Published in-print
DOI jem.20110345 [pii] 10.1084/jem.20110345
URL link to publisher's version
OpenAccess link to author's accepted manuscript version