DOCK8 is essential for T-cell survival and the maintenance of CD8+ T-cell memory.

Journal article

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: Lambe, T; Crawford, G; Johnson, A; Crockford, T; Bouriez-Jones, T

• Publication status: Published
• Journal: European journal of immunology
• Volume: 41
• Issue: 12
• Pages: 3423-3435
• Publication date: 2011-12-01
• DOI: 10.1002/eji.201141759
• EISSN: 1521-4141
• ISSN: 0014-2980
• Language: English
• Keywords: CD8-Positive T-Lymphocytes; Lymphoma, T-Cell; Chemokine CXCL12; Cell Movement; Mice, Inbred C57BL; Immunologic Deficiency Syndromes; Cells, Cultured; Mice; Guanine Nucleotide Exchange Factors; Immunologic Memory; Orthomyxoviridae Infections; CD4-Positive T-Lymphocytes; Humans; Cell Survival; Animals; Lymphocyte Activation