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Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis.

ABSTRACT: Wiskott-Aldrich syndrome protein (WASp) is essential for optimal T cell activation. Patients with WAS exhibit both immunodeficiency and a marked susceptibility to systemic autoimmunity. We investigated whether alterations in Treg function might explain these paradoxical observations. While WASp-deficient (WASp(-/-)) mice exhibited normal thymic Treg generation, the competitive fitness of peripheral Tregs was severely compromised. The total percentage of forkhead box P3-positive (Foxp3(+)) Tregs among CD4(+) T cells was reduced, and WASp(-/-) Tregs were rapidly outcompeted by WASp(+) Tregs in vivo. These findings correlated with reduced expression of markers associated with self-antigen-driven peripheral Treg activation and homing to inflamed tissue. Consistent with these findings, WASp(-/-) Tregs showed a reduced ability to control aberrant T cell activation and autoimmune pathology in Foxp3(-/-)Scurfy (sf) mice. Finally, WASp(+) Tregs exhibited a marked selective advantage in vivo in a WAS patient with a spontaneous revertant mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS.

SUBMITTER: Humblet-Baron S

PROVIDER: S-EPMC1764857 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans.

Project description:Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21(low) B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients.

| S-EPMC4012141 | biostudies-literature

The Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells.

Project description:The Wiskott-Aldrich syndrome, a primary human immunodeficiency, results from defective expression of the hematopoietic-specific cytoskeletal regulator Wiskott-Aldrich syndrome protein (WASP). Because CD4(+)CD25(+)Foxp3(+) naturally occurring regulatory T (nTreg) cells control autoimmunity, we asked whether colitis in WASP knockout (WKO) mice is associated with aberrant development/function of nTreg cells. We show that WKO mice have decreased numbers of CD4(+)CD25(+)Foxp3(+) nTreg cells in both the thymus and peripheral lymphoid organs. Moreover, we demonstrate that WKO nTreg cells are markedly defective in both their ability to ameliorate the colitis induced by the transfer of CD45RB(hi) T cells and in functional suppression assays in vitro. Compared with wild-type (WT) nTreg cells, WKO nTreg cells show significantly impaired homing to both mucosal (mesenteric) and peripheral sites upon adoptive transfer into WT recipient mice. Suppression defects may be independent of antigen receptor-mediated actin rearrangement because both WT and WKO nTreg cells remodeled their actin cytoskeleton inefficiently upon T cell receptor stimulation. Preincubation of WKO nTreg cells with exogenous interleukin (IL)-2, combined with antigen receptor-mediated activation, substantially rescues the suppression defects. WKO nTreg cells are also defective in the secretion of the immunomodulatory cytokine IL-10. Overall, our data reveal a critical role for WASP in nTreg cell function and implicate nTreg cell dysfunction in the autoimmunity associated with WASP deficiency.

| S-EPMC2118715 | biostudies-literature

The Wiskott-Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation.

Project description:The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)+ CD4+ CD8+ double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8+ SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation.

| S-EPMC10282776 | biostudies-literature

Defective inhibition of B-cell proliferation by Wiskott-Aldrich syndrome protein-deficient regulatory T cells.

Project description:Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency characterized by high incidence of autoantibody-mediated autoimmune complications. Such a feature has been associated with defective suppressor activity of WAS protein-deficient, naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T cells on responder T cells. However, it remains to be established whether the altered B-cell tolerance reported in WAS patients and Was knockout (WKO) mice is secondary to abnormalities in the direct suppression of B-cell function by nTreg cells or to impaired regulation of T-helper function. Because activated nTreg cells are known to induce granzyme B-mediated B-cell killing, we decided to evaluate the regulatory capabilities of WKO nTregs on B lymphocytes. We found that preactivated WKO nTreg cells failed to effectively suppress B-cell proliferation and that such a defect was associated with reduced killing of B cells and significantly decreased degranulation of granzyme B. Altogether, these results provide additional mechanistic insights into the loss of immune tolerance in WAS.

| S-EPMC3123025 | biostudies-literature

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

Project description: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 WASp-deficient 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.

| S-EPMC1986664 | biostudies-literature

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells.

Project description:The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.

| S-EPMC7673780 | biostudies-literature

Wiskott-Aldrich syndrome protein is involved in alphaIIb beta3-mediated cell adhesion.

Project description:The Wiskott-Aldrich syndrome (WAS) is an X-chromosome-linked immunodeficiency disorder. The most common symptom seen in WAS patients is bleeding. One of the main causes of bleeding is defective platelet aggregation. The causative gene of WAS encodes WAS protein (WASP). Here, we show that WASP binds to the calcium- and integrin-binding protein (CIB) in platelets. CIB was originally identified as a protein binding to the alphaIIb cytoplasmic tail of platelet integrin alphaIIb beta3, which has a primary role in platelet aggregation. We also show that the WASP-CIB complex is important in alphaIIb beta3-mediated cell adhesion, and that in patients mutant forms of WASP are expressed at reduced levels or show lower affinities for CIB than wild-type WASP. Our results indicate that impaired complex formation between mutant WASPs and CIB reduces alphaIIb beta3-mediated cell adhesion and causes defective platelet aggregation, resulting in bleeding.

| S-EPMC1479562 | biostudies-literature

IL-17-Dependent Dysregulated Cutaneous Immune Homeostasis in the Absence of the Wiskott-Aldrich Syndrome Protein.

Project description:Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the 'itch' factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.

| S-EPMC8900519 | biostudies-literature

Stem-cell gene therapy for the Wiskott-Aldrich syndrome.

Project description:The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder associated with thrombocytopenia, eczema, and autoimmunity. We treated two patients who had this disorder with a transfusion of autologous, genetically modified hematopoietic stem cells (HSC). We found sustained expression of WAS protein expression in HSC, lymphoid and myeloid cells, and platelets after gene therapy. T and B cells, natural killer (NK) cells, and monocytes were functionally corrected. After treatment, the patients' clinical condition markedly improved, with resolution of hemorrhagic diathesis, eczema, autoimmunity, and predisposition to severe infection. Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis. (Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00000330.).

| S-EPMC3064520 | biostudies-literature

Wiskott-Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma.

Project description:In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-β. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.

| S-EPMC6556382 | biostudies-literature

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