Steven F. Ziegler, Ph.D.
Affiliate Associate Professor, Immunology

Benaroya Research Institute at Virginia Mason
1201 Ninth Avenue
Seattle, WA 98101-2795
Tel: 206.344-7950
Fax: 206.223-7543
email: sziegler@benaroyaresearch.org

Ziegler Lab Web Page at VMRC

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. He is also an Affiliate Professor in the Department of Immunology.

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

1. 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.

a) Structure/function analysis of FoxP3. We have shown that FoxP3 functions as a transcriptional repressor, targeting composite NF-AT/AP-1 sites in cytokine gene promoters. 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 mapped the region responsible for NF-AT inhibition to the amino terminus of FoxP3. We are currently examining the mechanism of FoxP3-mediated NF-AT inhibition, and the role of this amino terminal domain of FoxP3 in this process.

b) 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.

c) 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.

2. 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, gut, and thymus. 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.

Students currently training in the Ziegler Lab: Mark Headley, Ryan Larson, Michael Miazgowicz

Representative publications:

Schubert, L.S., Jeffery, E., Zhang, Y., Ramsdell, F., and Ziegler, S.F. (2001). Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem. 276: 37672-37679.

Kasprowicz, D.J., Smallwood, P. S., Tyznik, A.J., and Ziegler, S.F. (2003). Scurfin (FoxP3) regulates T cell function in a T-dependent immune response in vivo. J. Immunol. 171:1216-1223.

Walker, M.R., Kasprowicz, D.J., Gersuk, V.H., Benard, A., Van Landeghen, M., Buckner, J.H., and Ziegler, S.F. (2003). Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J. Clin Invest. 112:1437-1443.

Walker, M.R., Carson, B., Nepom, G.T., Ziegler, S.F., and Buckner, J.H. (2005). De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. Proc. Natl. Acad. Sci. USA. 102:4103-4108.

Yoo, J., Omori, M., Gyarmati, D., Aye, T., Branstatter, D.G., Comeau, M.R., Campbell, D.J., and Ziegler, S.F. (2005). Spontaneous Atopic Dermatitis in Mice Expressing an Inducible Thymic Stromal Lymphopoietin (TSLP) Transgene Specifically in the Skin. J. Exp. Med. 202:541-549.

Zhou, B., Comeau, M.R., De Smedt, T., Liggitt, H.D., Dahl, M.E., Lewis, D.B., Gyarmati, D.,Aye, T., Campbell, D.J., and Ziegler, S.F. (2005). Thymic stromal lymphopoietin as key initiator of allergic airway inflammation in mice. Nature Immunology. 6:1047-1053

Lee. H-C., and Ziegler, S.F. (2006). Inducible Expression of the Proallergic Cytokine Thymic Stromal Lymphopoietin in Airway Epithelial Cells Is Controlled by NFkB. Proc Nat Acad Sci (USA). 104:914-919.

Humblet-Baron, S., Sather, B., Anover, S., Becker-Herman, S., Kasprowicz, D.J., Khim, S., Nguyen T., Hudkins-Loya, K., Alpers, C.E., Ziegler, S.F., Ochs H., Torgerson, T.R., Campbell, D.J., Rawlings, D.J. (2006). Wiskott Aldrich Syndrome Protein is required for regulatory T cell homeostasis. J Clin Invest. 117:407-418.

Lopes, J.E.*, Torgerson, T.R.*, Schubert, L.A., Anover, S.D., Ochs, H.D., and Ziegler, S.F. (2006). Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J. Immunol. 177:3133-3142.

Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF, Mathis D, Benoist C, Chen L, Rao A. (2006). FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT. Cell. 126:375-387.

Ziegler, S.F. and Liu, Y-J. (2006). Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat. Immunol. 7:709-714.

Omori, M. and Ziegler, S.F. (2007). Induction of IL-4 Expression in CD4+ T cells by Thymic Stromal Lymphopoietin (TSLP). J. Immunol. 178:1396-1404.

Soper, D.M., Kasprowicz, D.J., and Ziegler, S.F. (2007). IL-2Rbeta links IL-2R signaling with Foxp3 expression. Eur J Immunol. 37:1817-26.

Campbell, D.J. and Ziegler, S.F. (2007). FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nat Rev Immunol. 7:305-310

Updated 7/11/07