Nuclear Role of WASp in the Pathogenesis of Dysregulated TH1 Immunity in Human Wiskott-Aldrich Syndrome

Nuclear role for WASp in T-BET transcription. Nuclear Face of WASp For nearly 15 years, the protein gone awry in the hereditary disease affecting young boys known as Wiskott-Aldrich syndrome, WASp, has been linked to its role in maintaining the cellular architecture by reorganizing actin filaments in response to specific signals. Patients affected by the disease develop immunological deficiencies, ranging from eczema and frequent infections, to fatal malignancies such as lymphomas and leukemias, ending the lives of these patients usually by the unripe age of 30. At the cellular and molecular level, the blood obtained from these WAS patients exhibited abnormal actin bundling properties within T lymphocytes, and it was postulated that the ability of WASp to reorganize actin is dependent upon the activation and binding of Cdc42 in response to extra-cellular stimuli. However, while speculations based on biochemical and structural motif analyses have hinted at alternative roles for WASp within the cell, the exact mechanism by which this is or is not the case has not been reported. Now, Yatin Vyas and colleagues take a closer look at the cells from WAS patients and uncover the nuclear face of WASp. In this study, nuclear WASp is directly involved at the transcriptional level by ensuring the precise acquisition of chromatin marks required for the differentiation of T helper 1 (TH1) cells or type 1 immunity, but not of TH2 cells, explaining the tipped balance between these two cell populations central to the immune deficiencies in WAS patients. Epigenetic regulation of T cell differentiation linked to cancerous malignancies offers an appealing avenue for targeted therapeutic intervention of this multifaceted protein. The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (TH1) immunity alongside intact TH2 immunity. This suggests a role for WASp in patterning TH subtype immunity, yet the molecular basis for the TH1-TH2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the TH1 regulator gene TBX21 at the chromatin level. In primary TH1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the TBX21 gene, but not to the core promoter of GATA3 (a TH2 regulator gene) or RORc (a TH17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates TH1 cell fate choice in the human TH cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the TBX21 proximal promoter in primary differentiating TH1 cells. During TH1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the TBX21 proximal promoter locus. Accordingly, human WASp-deficient TH cells, from natural mutation or RNA interference–mediated depletion, demonstrate repressed TBX21 promoter dynamics when driven under TH1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired TH1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a previously unappreciated role of WASp in the epigenetic control of T-BET transcription and provide a new mechanism for the pathogenesis of WAS by linking aberrant histone methylation at the TBX21 promoter to dysregulated adaptive immunity.