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

• Published in: The Journal of experimental medicine 2011-10, Vol.208 (11), p.2305-2320
• Main Authors: Randall, Katrina L, Chan, Stephanie S-Y, Ma, Cindy S, Fung, Ivan, Mei, Yan, Yabas, Mehmet, Tan, Andy, Arkwright, Peter D, Al Suwairi, Wafaa, Lugo Reyes, Saul Oswaldo, Yamazaki-Nakashimada, Marco A, Garcia-Cruz, Maria de la Luz, Smart, Joanne M, Picard, Capucine, Okada, Satoshi, Jouanguy, Emmanuelle, Casanova, Jean-Laurent, Lambe, Teresa, Cornall, Richard J, Russell, Sarah, Oliaro, Jane, Tangye, Stuart G, Bertram, Edward M, Goodnow, Christopher C
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - physiology; Cell Differentiation - physiology; Cell Division - physiology; Cell Proliferation; Cell Survival - immunology; Guanine Nucleotide Exchange Factors - deficiency; Humans; Immunologic Deficiency Syndromes - immunology; Immunologic Memory - immunology; Immunological Synapses - immunology; Influenza virus; Lymphocyte Activation - immunology; Lymphocyte Function-Associated Antigen-1 - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Orthomyxoviridae - physiology; Phenotype; Transplantation Chimera
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20110345

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.