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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 (T_H1) immunity alongside intact T_H2 immunity. This suggests a role for WASp in patterning T_H subtype immunity, yet the molecular basis for the T_H1-T_H2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the T_H1 regulator gene TBX21 at the chromatin level. In primary T_H1-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 T_H2 regulator gene) or RORc (a T_H17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that …