title: DOCK8 is essential for T-cell survival and the maintenance of CD8+ T-cell memory.
abstract: Deficiency in the guanine nucleotide exchange factor dedicator of cytokinesis 8 (DOCK8) causes a human immunodeficiency syndrome associated with recurrent sinopulmonary and viral infections. We have recently identified a DOCK8-deficient mouse strain, carrying an ethylnitrosourea-induced splice-site mutation that shows a failure to mature a humoral immune response due to the loss of germinal centre B cells. In this study, we turned to T-cell immunity to investigate further the human immunodeficiency syndrome and its association with decreased peripheral CD4(+)  and CD8(+)  T cells. Characterisation of the DOCK8-deficient mouse revealed T-cell lymphopenia, with increased T-cell turnover and decreased survival. Egress of mature CD4(+)  thymocytes was reduced with increased migration of these cells to the chemokine CXCL12. However, despite the two-fold reduction in peripheral naïve T cells, the DOCK8-deficient mice generated a normal primary CD8(+)  immune response and were able to survive acute influenza virus infection. The limiting effect of DOCK8 was in the normal survival of CD8(+)  memory T cells after infection. These findings help to explain why DOCK8-deficient patients are susceptible to recurrent infections and provide new insights into how T-cell memory is sustained.
authors.affiliation: Nuffield Department of Medicine, Henry Wellcome Building of Molecular Physiology, Oxford University, Oxford, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lambe
authors.forename: Greg
authors.initials: G
authors.lastname: Crawford
authors.forename: Andy L
authors.initials: AL
authors.lastname: Johnson
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Crockford
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Bouriez-Jones
authors.forename: Aisling M
authors.initials: AM
authors.lastname: Smyth
authors.forename: Trung H M
authors.initials: TH
authors.lastname: Pham
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
authors.forename: Helen C
authors.initials: HC
authors.lastname: Su
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C516591:DOCK8 protein, human; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors