title: Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells.
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.
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.|Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany.
authors.forename: Marisa A P
authors.initials: MA
authors.lastname: Baptista
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Marton
authors.initials: M
authors.lastname: Keszei
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Mariana
authors.initials: M
authors.lastname: Oliveira
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.|Experimental Physiopathology, Department of Sciences/Experimental Physiopatholgy, Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Karen K S
authors.initials: KK
authors.lastname: Sunahara
authors.affiliation: Department of Medicine Solna, Translational Immunology Unit, Karolinska Institutet and Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Andersson
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Carin I M
authors.initials: CI
authors.lastname: Dahlberg
authors.affiliation: University College London Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Austen J
authors.initials: AJ
authors.lastname: Worth
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Agne
authors.initials: A
authors.lastname: Liedén
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.|Khoo Teck Puat-National University Children's Medical Institute, The National University Health System, Singapore 119228, Singapore.
authors.forename: I-Chun
authors.initials: IC
authors.lastname: Kuo
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Robert P A
authors.initials: RP
authors.lastname: Wallin
authors.affiliation: Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston MA 02115, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.affiliation: Department of Medicine Solna, Dermatology and Venereology Unit, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Liv
authors.initials: L
authors.lastname: Eidsmo
authors.affiliation: Department of Medicine Solna, Translational Immunology Unit, Karolinska Institutet and Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Scheynius
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Mikael C I
authors.identifier: 0000-0001-5582-614X
authors.initials: MC
authors.lastname: Karlsson
authors.affiliation: University College London Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Gerben
authors.initials: G
authors.lastname: Bouma
authors.affiliation: University College London Institute of Child Health, London WC1N 1EH, UK.|Department of Immunology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.|University College London Institute of Immunity and Transplantation, London WC1E 6BT, UK.
authors.forename: Siobhan O
authors.initials: SO
authors.lastname: Burns
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.|Department of Clinical Microbiology, Division of Immunology, Umeå University, Umeå 901 87, Sweden.
authors.forename: Mattias N E
authors.initials: MN
authors.lastname: Forsell
authors.affiliation: University College London Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Nylén
authors.affiliation: Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm 171 77, Sweden.
authors.forename: Lisa S
authors.identifier: 0000-0003-2943-2192
authors.initials: LS
authors.lastname: Westerberg
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000378:metabolism; D060829:Arthropod Proteins / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology; D049109:Cell Proliferation; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D017353:Gene Deletion; D007371:Interferon-gamma / Q000378:metabolism; D018320:Leishmania major / Q000502:physiology; D018655:Lymphocyte Count; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010588:Phagosomes / Q000378:metabolism; D000072417:Protein Domains; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D007371:Interferon-gamma; D017382:Reactive Oxygen Species; D051316:Wiskott-Aldrich Syndrome Protein; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C451163:Dermatophagoides pteronyssinus antigen p 2