The Wiskott-Aldrich Syndrome Protein Acts Downstream of CD2 and the CD2AP and PSTPIP1 Adaptors to Promote Formation of the Immunological Synapse

Badour, Karen; Zhang, Jinyi; Shi, Fabio; McGavin, Mary K. H.; Rampersad, Vik; Hardy, Lynne A; Field, Deborah J.; Siminovitch, Katherine A.

doi:10.1016/s1074-7613(02)00516-2

Cited by 182 publications

(189 citation statements)

References 57 publications

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“…Treg cell suppression function depends on TCR stimulation (40) and requires direct cell-cell interaction (41). WASp deficiency is associated with defective TCR-mediated activation and impaired formation of the immunological synapse (6)(7)(8)(9)(42)(43)(44), both of which may affect Treg cell suppression activity. Interestingly, the partial rescue of in vitro suppression defects by pre-activation of WASp-deficient Treg cells with IL-2, suggests that optimization of T cell activation may overcome the defect of WAS Treg cells.…”

Section: Discussionmentioning

confidence: 99%

Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome

Adriani

Aoki

Horai

et al. 2007

Clinical Immunology

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Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency characterized by the contradictory coexistence of impaired T-cell function and exaggerated T-cell-mediated pathology, including autoimmunity and eczema. WAS protein (WASp)-deficient mice are also immunodeficient and can develop autoimmune disease. Since defects in regulatory T-cells (Treg) are associated with autoimmunity, we examined the presence and function of these cells in WAS patients and WASpdeficient mice. We found that CD4 + CD25 + FOXP3 + Treg cells can develop in the absence of WASp expression. However, Treg cells both from WASp-deficient mice and from four out of five WAS patients studied showed impaired in vitro suppressor function. In WASp-deficient mice, this defect could be partially rescued by pre-activation with IL-2, suggesting that inadequate cell activation may play a role in WASp-deficient Treg dysfunction. These findings may provide insights into the complex pathophysiology and paradoxical phenotypes of WAS and suggest new therapeutic modalities for autoimmunity in these patients.

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Section: Discussionmentioning

confidence: 99%

Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome

Adriani

Aoki

Horai

et al. 2007

Clinical Immunology

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“…5D). CD2AP, another important mediator of TCR-induced actin polymerization (Badour et al, 2003), also accumulated at the IS in non-silenced SEE-challenged T cells, and this accumulation was impaired in clathrin KD T cells (Fig. 5E).…”

Section: Clathrin Is Necessary For Recruitment Of Key Adaptor and Regmentioning

confidence: 95%

Endosomal clathrin drives actin accumulation at the immunological synapse

Calabia-Linares

Robles‐Valero

Fuente

et al. 2011

Journal of Cell Science

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SummaryAntigen-specific cognate interaction of T lymphocytes with antigen-presenting cells (APCs) drives major morphological and functional changes in T cells, including actin rearrangements at the immune synapse (IS) formed at the cell-cell contact area. Here we show, using cell lines as well as primary cells, that clathrin, a protein involved in endocytic processes, drives actin accumulation at the IS. Clathrin is recruited towards the IS with parallel kinetics to that of actin. Knockdown of clathrin prevents accumulation of actin and proteins involved in actin polymerization, such as dynamin-2, the Arp2/3 complex and CD2AP at the IS. The clathrin pool involved in actin accumulation at the IS is linked to multivesicular bodies that polarize to the cell-cell contact zone, but not to plasma membrane or Golgi complex. These data underscore the role of clathrin as a platform for the recruitment of proteins that promote actin polymerization at the interface of T cells and APCs.

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“…WASp is a 502-amino acid member of a conserved family of proteins that participate in the organization of actin polymerization primarily through activation of the actin-related protein (Arp2/Arp3) complex. [10][11][12] Interference in these signaling pathways results in multiple cytoskeletal defects in DCs, including the failure to form normal membrane projections and specialized structures known as podosomes, which form behind the leading edge of motile cells. [13][14][15][16] Podosomes concentrate ␤2 integrins around an actin core and, although their function has not been clearly identified, are responsible for tight adhesion of cells to intercellular adhesion molecule-1 (ICAM-1) and possibly junctional adhesion molecule-A (JAM-A).…”

Section: Introductionmentioning

confidence: 99%

Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein

Noronha

2005

Blood

109

102

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IntroductionDendritic cells (DCs) are highly motile bone marrow-derived antigen-presenting cells (APCs). They have specialized migratory and homing properties that allow them both to initiate primary immune responses and to induce tolerance. 1,2 In lymphoid organs they are present as interdigitating cells in the white pulp of the spleen and in the paracortex of lymph nodes (LNs) where they are able to capture incoming foreign antigen from blood or lymph, respectively. In nonlymphoid tissues DCs act as sentinels of injury and patrol for the presence of foreign antigens and pathogens. Upon capture they migrate to draining secondary lymphoid tissue during which time they mature and develop the capacity to stimulate antigen specific T cells.The migration and spatial localization of DCs are controlled by numerous extrinsic factors, including chemokine family members to which they are responsive through maturation and localizationdependent mechanisms. [3][4][5][6][7] The physical motility of cells and anchorage in specific tissues is, however, ultimately dependent on the regulated dynamics of the actin cytoskeleton, which determines the response of cells to chemokine gradients and enables purposeful movement through the sequential process of leading-edge protrusion, attachment, and tail retraction. 8 The molecular control of this highly coordinated activity is orchestrated by Rho family guanosine triphosphatases (GTPases), the best characterized of which are Cdc42, Rac1/2, and RhoA, and their downstream effectors. 9 In hematopoietic cells, a key effector for Cdc42 is the Wiskott-Aldrich syndrome protein (WASp). WASp is a 502-amino acid member of a conserved family of proteins that participate in the organization of actin polymerization primarily through activation of the actin-related protein (Arp2/Arp3) complex. [10][11][12] Interference in these signaling pathways results in multiple cytoskeletal defects in DCs, including the failure to form normal membrane projections and specialized structures known as podosomes, which form behind the leading edge of motile cells. [13][14][15][16] Podosomes concentrate ␤2 integrins around an actin core and, although their function has not been clearly identified, are responsible for tight adhesion of cells to intercellular adhesion molecule-1 (ICAM-1) and possibly junctional adhesion molecule-A (JAM-A). [17][18][19] Furthermore, they are highly dynamic with a turnover of minutes, providing a migrating cell with a mechanism for rapid attachment and detachment, and with localized anchorage points that could facilitate traverse of endothelial barriers in particular.Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, eczema, and autoimmunity. 12 The pathophysiology of WAS relates to defective polymerization of [20][21][22][23][24][25][26] However, defects of migration identified in myeloid and T cells in vitro, and stem cells in vivo, [27][28][29][30][31] all support the hypothesis that many of the immunologic consequences of WASp deficiency ar...

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The Wiskott-Aldrich Syndrome Protein Acts Downstream of CD2 and the CD2AP and PSTPIP1 Adaptors to Promote Formation of the Immunological Synapse

Cited by 182 publications

References 57 publications

Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome

Impaired in vitro regulatory T cell function associated with Wiskott–Aldrich syndrome

Endosomal clathrin drives actin accumulation at the immunological synapse

Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein

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