Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells

- STAT5A or STAT5B were knocked down in human T cells via siRNA transfection.
- FOXP3 and IL-2R expression were down-regulated only in STAT5B knockdown T cells.
- Bcl-X expression was down-regulated only in STAT5A knockdown T cells.
- STAT5B−/− patients' Treg had reduced FoxP3 expression and regulatory function.
- STAT5B−/− patients' Treg also had increased memory phenotype.

STAT5A and STAT5B are highly homologous proteins whose distinctive roles in human immunity remain unclear. However, STAT5A sufficiency cannot compensate for STAT5B defects, and human STAT5B deficiency, a rare autosomal recessive primary immunodeficiency, is characterized by chronic lung disease, growth failure and autoimmunity associated with regulatory T cell (Treg) reduction. We therefore hypothesized that STAT5A and STAT5B play unique roles in CD4+ T cells. Upon knocking down STAT5A or STAT5B in human primary T cells, we found differentially regulated expression of FOXP3 and IL-2R in STAT5B knockdown T cells and down-regulated Bcl-X only in STAT5A knockdown T cells. Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype. These results indicate that STAT5B and STAT5A act partly as non-redundant transcription factors and that STAT5B is more critical for Treg maintenance and function in humans.