Abstract
Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8+ T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFNγ-producing CD8+ T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8+ T cells at the expense of CD4+ T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8+ T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.
Highlights
Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WAS protein (WASp) gene
We propose that deletion of key proteins, such as WASp, in patients and mice may induce alternative signalling pathways for cell survival and function that leads to altered biological responses
This study did not distinguish between changes in uptake of ovalbumin complexed with anti-DEC205 antibodies by WASp KO CD8 þ dendritic cells (DCs) and changes in presentation of major histocompatibility (MHC) class I—ovalbumin peptides by WASp KO CD8 þ DCs13
Summary
Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. We identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac[2] that support cross-presentation to CD8 þ T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFNg-producing CD8 þ T cells in the draining lymph node and spleen. WASp-deficient dendritic cells induce increased cross-presentation to CD8 þ T cells by activating Rac[2] that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac[2] signalling pathways in dendritic cells. Upon binding of the small Rho GTPase Cdc[42], the auto-inhibited conformation is released and exposes the carboxy-terminal verprolin-cofilin-acidic (VCA) domain that allows for recruitment of the Arp2/3 complex and actin polymerization[14,15]. Our data suggests that downregulation of cross-presentation by WASp may be an active process that is essential to prevent over-activation of CD8 þ T cells
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