Steven F. Ziegler, Ph.D.

Dr. Ziegler graduated with honors from the University of Michigan in 1979,and in 1984 received his Ph.D. in Molecular Biology from UCLA. Following post-doctoral training at the University of Washington, Dr. Ziegler spent five years as a staff scientist at Immunex, followed by three years as the Director of Immunology/Molecular Biology at Darwin Molecular. He joined the Benaroya Research Institute at Virginia Mason in 1997, where he is now a Full Member and the Director of the Immunology Program.

RESEARCH

The laboratory is interested in the underlying mechanisms that control the development and function of the immune system. The lab works on two areas:

FoxP3 and the control of CD4+CD25+ regulatory T cell development and function. The forkhead-family transcription factor FoxP3 has been implicated in the development and function of CD4+CD25+ regulatory T cells (Tregs). In the mouse, FoxP3 expression is both necessary and sufficient for generating Tregs, while FoxP3 expression has been shown to correlate with Treg function in humans. My laboratory is taking several approaches to better understand the role of this protein.

1. Structure/function analysis of FoxP3. We have taken advantage of mutations in the FoxP3 gene found in human patients with IPEX (Immune dysfunction/Polyendocrinopathy/Enteropathy/X-linked) syndrome to study the function of FoxP3. Using these mutations, as well as deletions, we have isolated and characterized several FOXP3-interacting proteins, and are now studying the role of these proteins in FOXP3 function.
2. Consequences of ectopic FoxP3 expression. Previous work has shown that introduction of FoxP3 into conventional mouse T cells converts these T cells to a Treg-like phenotype. We have developed mice that express tetracycline-inducible FoxP3 transgenes in order to assess whether constant FoxP3 expression is needed for Treg function. We have just developed these mice, and preliminary data suggests that T cell phenotype correlates with expression of the inducible transgene.
3. Treg/Th17 differentiation. We have found that Foxp3 can interact with and inhibit the transcriptional factor RORgt. RORgt is required for the development of Th17 cells, which have been shown to be involved in autoimmune inflammatory responses. We are currently studying the interaction between Foxp3 and RORgt and its role in determining the differentiative decision between the Treg and Th17 lineages.

TSLP and allergic inflammation. We are also studying a cytokine called thymic stromal lymphopoietin (TSLP). TSLP is an IL-7-like cytokine that is expressed by epithelial cells in the lung, skin, and gut. Recent work has shown that TSLP can stimulate a wide variety of hematopoietically-derived cells, including dendritic cells, macrophages, CD4 T cells and B cells. Our lab has shown that TSLP responses are absolutely required for the development of Th2-type immunity in mice. In support of its role in allergic inflammation, keratinocytes from patients with atopic dermatitis produce high levels of TSLP, while keratinocytes from normal individuals do not. We have modeled human allergic diseases using transgenic mice that express TSLP at specific sites. Thus far we have mice that express an inducible TSLP transgenes in the skin and lungs. In both cases the mice develop the corresponding disease when the transgene is expressed-atopic dermatitis in the skin and asthma in the lung. We have also shown that TSLP is absolutely required for antigen-induced asthma in the mouse, demonstrating that this cytokine is both necessary and sufficient for allergic asthma. We have begun to analyze human patients with a variety of pulmonary inflammation diseases and have found TSLP to be at elevated levels. TSLP blockade is now being evaluated as a therapeutic tool in these diseases. Current studies include an analysis of the regulation of TSLP gene expression, signal transduction from the TSLP receptor, and the identification and characterization of downstream mediators of TSLP-mediated inflammation. We are also using model systems to understand the role of TSLP in allergic disease and in respiratory virus infection.

PUBLICATIONS

1. Kitajima M, Lee HC, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. Eur J Immunol. 2011 Jul;41(7):1862-71. doi: 10.1002/eji.201041195. Epub 2011 Jun 7.
2. Thompson LJ, Valladao AC, Ziegler SF. Cutting edge: De novo induction of functional Foxp3+ regulatory CD4 T cells in response to tissue-restricted self antigen. J Immunol. 2011 Apr 15;186(8):4551-5. Epub 2011 Mar 14.
3. Ziegler SF. The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol. 2010 Dec;22(6):795-9. Epub 2010 Nov 23. Review.
4. Wesley JD, Sather BD, Perdue NR, Ziegler SF, Campbell DJ. Cellular requirements for diabetes induction in DO11.10xRIPmOVA mice. J Immunol. 2010 Oct 15;185(8):4760-8. Epub 2010 Sep 20.
5. Ziegler SF, Artis D. Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol. 2010 Apr;11(4):289-93. Review.