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

Katrina L. Randall, Stephanie S Y Chan, Cindy S. Ma, Ivan Fung, Yan Mei, Mehmet Yabas, Andy Tan, Peter D. Arkwright, Wafaa Al Suwairi, Saul Oswaldo Lugo Reyes, Marco A. Yamazaki-Nakashimada, Maria de la Luz Garcia-Cruz, Joanne M. Smart, Capucine Picard, Satoshi Okada, Emmanuelle Jouanguy, Jean Laurent Casanova, Teresa Lambe, Richard J. Cornall, Sarah RussellJane Oliaro, Stuart G. Tangye, Edward M. Bertram, Christopher C. Goodnow

    Research output: Contribution to journalArticlepeer-review


    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 languageEnglish
    Pages (from-to)2305-2320
    Number of pages15
    JournalJournal of Experimental Medicine
    Issue number11
    Publication statusPublished - 24 Oct 2011


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