Marisa A.P. Baptista, Marton Keszei, Mariana Oliveira, Karen K.S. Sunahara, John Andersson, Carin I.M. Dahlberg, Austen J. Worth, Agne Liedén, I-Chun Kuo, Robert P.A. Wallin, Scott B. Snapper, Liv Eidsmo, Annika Scheynius, Mikael C.I. Karlsson, Gerben Bouma, Siobhan O. Burns, Mattias N.E. Forsell, Adrian J. Thrasher, Susanne Nylén, Lisa S. Westerberg

• Wiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in theWASp 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 CD8þ T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin andWiskott–Aldrich syndrome (WAS) is caused by loss-of-function mutations in theWASp 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 CD8þ 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 CD8þ T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8þ T cells at the expense of CD4þ T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8þ 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.…