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

T Lambe, G Crawford, AL Johnson… - European journal of …, 2011 - Wiley Online Library
T Lambe, G Crawford, AL Johnson, TL Crockford, T Bouriez‐Jones, AM Smyth, THM Pham
European journal of immunology, 2011Wiley Online Library
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 …
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 naļve 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.
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