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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.

Original publication

DOI

10.1084/jem.20110345

Type

Journal article

Journal

J Exp Med

Publication Date

24/10/2011

Volume

208

Pages

2305 - 2320

Keywords

Animals, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Division, Cell Proliferation, Cell Survival, Guanine Nucleotide Exchange Factors, Humans, Immunologic Deficiency Syndromes, Immunologic Memory, Immunological Synapses, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Orthomyxoviridae, Phenotype, Transplantation Chimera