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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4278-4284.
Prepublished online as a Blood First Edition Paper on August 2, 2007; DOI 10.1182/blood-2007-06-096875.
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IMMUNOBIOLOGY
Impaired T-cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells
Gerben Bouma1,
Siobhan Burns1,2, and
Adrian J. Thrasher1,2
1 Institute of Child Health, University College London (UCL), Molecular Immunology Unit, London; and
2 Great Ormond Street Hospital for Children National Health Service Trust, London, United Kingdom
The Wiskott-Aldrich syndrome (WAS) is characterized by defective cytoskeletal dynamics affecting multiple immune cell lineages, and leading to immunodeficiency and autoimmunity. The contribution of dendritic cell (DC) dysfunction to the immune dysregulation has not been defined, although both immature and mature WAS knockout (KO) DCs exhibit significant abnormalities of chemotaxis and migration. To exclude environmental confounders as a result of WAS protein (WASp) deficiency, we studied migration and priming activity of WAS KO DCs in vivo after adoptive transfer into wild-type recipient mice. Homing to draining lymph nodes was reduced and WAS KO DCs failed to localize efficiently in T-cell areas. Priming of both CD4+ and CD8+ T lymphocytes by WAS KO DCs preloaded with antigen was significantly decreased. At low doses of antigen, activation of preprimed wild-type CD4+ T lymphocytes by WAS KO DCs in vitro was also abrogated, suggesting that there is a threshold-dependent impairment even if successful DC–T cell colocalization is achieved. Our data indicate that intrinsic DC dysfunction due to WASp deficiency directly impairs the T-cell priming response in vivo, most likely as a result of inefficient migration, but also possibly influenced by suboptimal DC-mediated cognate interaction.
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