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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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Submitted June 21, 2007
Accepted July 31, 2007
Impaired T cell priming in vivo resulting from dysfunction of WASp-deficient dendritic cells
Gerben Bouma, Siobhan Burns, and Adrian J. Thrasher*
Molecular Immunology Unit, Institute of Child Health, University College London, London, United Kingdom
Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom
* Corresponding author; email: a.thrasher{at}ich.ucl.ac.uk.
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 KO DC exhibit significant abnormalities of chemotaxis and migration. To exclude environmental confounders as a result of WASp deficiency, we studied migration and priming activity of WAS KO DC in vivo after adoptive transfer into wild type recipient mice. Homing to draining lymph nodes was reduced and WAS KO DC failed to localise efficiently in T cell areas. Priming of both CD4+ and CD8+ T lymphocytes by WAS KO DC pre-loaded with antigen was significantly decreased. At low doses of antigen, activation of pre-primed wild-type CD4+ T lymphocytes by WAS KO DC in vitro was also abrogated, suggesting that there is a threshold-dependent impairment even if successful DC-T cell co-localisation 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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