Wiskott-Aldrich Syndrome Interacting Protein Deficiency Uncovers the Role of the Co-receptor CD19 as a Generic Hub for PI3 Kinase Signaling in B Cells

Selina Jessica Keppler; Francesca Gasparrini; Marianne Burbage; Shweta Aggarwal; Bruno Frederico; Raif S Geha; Michael Way; Andreas Bruckbauer; Facundo D Batista

doi:10.1016/j.immuni.2015.09.004

Wiskott-Aldrich Syndrome Interacting Protein Deficiency Uncovers the Role of the Co-receptor CD19 as a Generic Hub for PI3 Kinase Signaling in B Cells

Immunity. 2015 Oct 20;43(4):660-73. doi: 10.1016/j.immuni.2015.09.004. Epub 2015 Oct 6.

Authors

Selina Jessica Keppler¹, Francesca Gasparrini¹, Marianne Burbage¹, Shweta Aggarwal¹, Bruno Frederico¹, Raif S Geha², Michael Way³, Andreas Bruckbauer¹, Facundo D Batista⁴

Affiliations

¹ Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
² Division of Immunology, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
³ Cell Motility Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
⁴ Lymphocyte Interaction Laboratory, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: facundo.batista@crick.ac.uk.

Abstract

Humans with Wiskott-Aldrich syndrome display a progressive immunological disorder associated with compromised Wiskott-Aldrich Syndrome Interacting Protein (WIP) function. Mice deficient in WIP recapitulate such an immunodeficiency that has been attributed to T cell dysfunction; however, any contribution of B cells is as yet undefined. Here we have shown that WIP deficiency resulted in defects in B cell homing, chemotaxis, survival, and differentiation, ultimately leading to diminished germinal center formation and antibody production. Furthermore, in the absence of WIP, several receptors, namely the BCR, BAFFR, CXCR4, CXCR5, CD40, and TLR4, were impaired in promoting CD19 co-receptor activation and subsequent PI3 kinase (PI3K) signaling. The underlying mechanism was due to a distortion in the actin and tetraspanin networks that lead to altered CD19 cell surface dynamics. In conclusion, our findings suggest that, by regulating the cortical actin cytoskeleton, WIP influences the function of CD19 as a general hub for PI3K signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton / ultrastructure
Actins / analysis
Animals
Antibody Formation
Antigens, CD19 / physiology*
B-Lymphocytes / drug effects
B-Lymphocytes / enzymology
B-Lymphocytes / immunology*
B-Lymphocytes / ultrastructure
Carrier Proteins / genetics
Carrier Proteins / physiology*
Cells, Cultured
Chemokines / pharmacology
Chemokines / physiology
Chemotaxis / drug effects
Cytoskeletal Proteins
Germinal Center / immunology
Germinal Center / pathology
Haptens
Hemocyanins / pharmacology
Lymphocyte Activation / drug effects
Lymphopoiesis
Membrane Proteins / immunology
Mice
Phosphatidylinositol 3-Kinases / physiology*
Phosphorylation
Plasma Cells / immunology
Protein Processing, Post-Translational
Radiation Chimera
Receptors, Antigen, B-Cell / immunology
Receptors, Chemokine / physiology
Signal Transduction / immunology*
Tetraspanins / analysis
Vaccinia / immunology
Vaccinia / pathology

Substances

4-hydroxy-3-nitrophenylacetyl-keyhole limpet hemocyanin
Actins
Antigens, CD19
Carrier Proteins
Chemokines
Cytoskeletal Proteins
Haptens
Membrane Proteins
Receptors, Antigen, B-Cell
Receptors, Chemokine
Tetraspanins
Waspip protein, mouse
Hemocyanins

Grants and funding

15691/CRUK_/Cancer Research UK/United Kingdom