Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity

Abstract

The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection. In this review we outline the cellular defects that have been characterized in both human WAS patients and murine models of the disease. We will emphasize in particular recent discoveries that provide a mechanistic insight into disease pathology, including lymphoid and myeloid cell homeostasis, immune synapse assembly and immune cell signaling.

Keywords: Autoimmunity; Immune synapse; Inflammation; Wiskott Aldrich syndrome; Wiskott Aldrich syndrome protein.

Figure 1

Domain structure of WASP in its inactive and active forms. At rest, WASP exists in an autoinhibited state where the VCA region associates with the GBD region, the conformation of which is stabilised by WIP. WASP becomes activated through binding partners such as the GTPase CDC42 or phosphorylation of a tyrosine residue (Y291), which release the VCA domain and expose the ARP 2/3 binding domain. The ARP 2/3 complex recruits actin monomers resulting in the formation of branched actin filaments. ARP 2/3, actin-related protein; B, basic domain; CDC42, cell division cycle 42; EVH1, Ena-VASP homology domain; GBD, guanosine triphosphate binding domain; P, phosphate; PP, polyproline domain; VCA, verprolin homology/central/acidic domain; WASP, Wiskott Aldrich syndrome protein; WIP, WASP interacting protein.

Figure 2. WASP deficiency and inflammation. Inflammatory symptoms are common in WAS and the role of WASP in inflammation is being increasingly defined.

(A) CD4⁺ T cells show impaired gene transcription required for T_H1 differentiation, leading to T_H2 dominance. Treg cells produce less of the anti-inflammatory cytokine IL-10 and fail to regulate T_H2 effector responses, which has been associated with allergic intestinal inflammation. Reduced numbers of IL-10 producing Breg cells are associated with reduced Treg cell recruitment and increased pro-inflammatory T_H17 cells. (B) Enhanced cross presentation leads to over activation of CD8⁺ T cells and is associated with skin inflammation, which is contributed to by allergen-laden Langerhans cells that fail to migrate from the skin to lymph nodes. Neutrophil migration to sites of sterile inflammation is also impaired, particularly through WASP-BTK interaction. (C) Increased numbers of pro-inflammatory macrophages are found, with increased production of pro-inflammatory cytokines. Breg cell, regulatory B cell; BTK, Bruton’s Tyrosine Kinase; DC, dendritic cell; LN, lymph node; T_H1/2/17, T helper cells; Treg cell, regulatory T cell; WAS, Wiskott Aldrich syndrome; WASP, Wiskott Aldrich syndrome protein.