DOCK8 is essential for T-cell survival and the maintenance of CD8 super(+) T-cell memory

• Published in: European journal of immunology 2011-12, Vol.41 (12), p.3423-3435
• Main Authors: Lambe, Teresa, Crawford, Greg, Johnson, Andy L, Crockford, Tanya L, Bouriez-Jones, Tiphaine, Smyth, Aisling M, Pham, Trung HM, Zhang, Qian, Freeman, Alexandra F, Cyster, Jason G, Su, Helen C, Cornall, Richard J
• Format: Article
• Language: English
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201141759

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 super(+) and CD8 super(+) T cells. Characterisation of the DOCK8-deficient mouse revealed T-cell lymphopenia, with increased T-cell turnover and decreased survival. Egress of mature CD4 super(+) thymocytes was reduced with increased migration of these cells to the chemokine CXCL12. However, despite the two-fold reduction in peripheral naive T cells, the DOCK8-deficient mice generated a normal primary CD8 super(+) immune response and were able to survive acute influenza virus infection. The limiting effect of DOCK8 was in the normal survival of CD8 super(+) 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.