Jianying Yang

E-mail: yang0935@umn.edu

Thesis Advisor: Mike Farrar

Year entered: 2003

Degrees received:
M.D., Internal Medicine, Beijing Medical University, Beijing, China 1996
M.S., Molecular Pathology, University of Wisconsin, Madison, WI 2003

Thesis research:
Mice lacking the interleukin 2 receptor beta chain (IL-2Rb) develop fatal autoimmune disease.  We have recently found that the ILRb chain is required for the development of regulatory T cells (Tregs).  To investigate the underlying molecular mechanisms by which IL-2Rb entrains Treg development, we generated a panel of IL-2Rb mutants that selectively activate either (i) STAT5, or (ii) Erk/PI3K signaling pathways. Using a retroviral transduction system, we have reconstituted IL-2Rb-/- mice with these distinct IL-2Rb constructs.  Reconstitution of IL-2Rb-/- bone marrow with either wild type IL-2Rb, or an IL-2Rb mutant that selectively activates STAT5, restored CD4+CD25+Foxp3+ Treg development.  In contrast, IL2Rb mutants that selectively activate the PI3K\Erk pathways did not restore Foxp3+ Tregs.  To further demonstrate that STAT5 activation is crucial for regulatory T cell development, we crossed CD4cre mice with STAT5Fl/Fl mice. The STAT5 deletion in these conditional STAT5 knockout mice resulted in a profound reduction of CD4+CD25+Foxp3+ T cells. Importantly, the residual CD4+CD25+ T cells in these mice uniformly expressed phospho-STAT5 after IL-2/IL-7 stimulation, demonstrating that the only Tregs that remained were those that had not deleted STAT5. In contrast, CD4+CD25- T cells showed efficient deletion of the STAT5 gene as demonstrated by the absence of phospho-STAT5 in these cells following IL-2/IL-7 stimulation. These findings suggest that STAT5 activation is stringently required for the development of Tregs. Taken together our findings suggest that STAT5 activation downstream of IL-2Rb is both necessary and sufficient to drive CD4+CD25+Foxp3+ T cell development. Our preliminary findings suggest that IL-2Rb-depenedent STAT5 activation acts in part via regulation of Foxp3 expression.