The principal focus of the Ziegler Laboratory is the development and regulation of the immune system. We are taking a variety of approaches, ranging from a detailed molecular analysis of gene expression to the generation of animal models of human autoimmune disease.
FoxP3 and the control of CD4+CD25+ Regulatory T Cell Development and Function
Regulatory T cells (Tregs) are a subset of CD4 T cells that are responsible for establishing and perpetuating peripheral tolerance. The Forkhead family transcription factor FOXP3 has been shown to be critical for the development and function of Tregs. Over the past several years our lab has been studying the function of FOXP3 in human Tregs, focusing on the proteins that interact with FOXP3. We have found that FOXP3 binds to and inhibits RORγt, thus regulating pTreg/Th17 differentiation. We have recently identified and characterized a novel, human-specific FOXP3 interacting protein that regulates the ability of FOXP3 to repress transcription. Current studies on this complex (FOXP3-FIK-KAP1 complex) involve an examination of genome-wide epigenetic changes when the complex is disrupted, and testing whether manipulating these interacting proteins can modulate FOXP3 function in disease models.
We have also found that bystander activation of CD4 T cells, which occurs during viral infections, can affect subsequent development decisions of those T cells. For example, exposure of naïve CD4 T cells to bystander inflammation (largely driven by type I interferon) can “prime” these cells to become Tregs when they subsequently encounter their cognate antigen. We are pursuing whether this effect can be used to generate more efficient human Tregs using in vitro methods.
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. We have generated a variety of mouse strains that exploit tissue-specific expression of TSLP to model human allergic disease, and have used these models to investigate the role of TSLP in these diseases (asthma and atopic dermatitis). We have also generated a conditional knockout of the TSLPR gene to identify and characterize the cell populations that respond to TSLP during allergen challenge, using known human allergens such as cockroach and Alternaria alternata. These studies have provided important preclinical data on the efficacy of TSLP blockade in these settings. We have begun to expand this work to include 2 other epithelial-derived cytokines that are also involved in allergic response, IL-25 and IL-33. These studies have begun and we have now found interesting and novel interactions between these cytokines in regulating responses to allergen challenge. In addition, in collaboration with Dr. Jason Debley (Seattle Children’s Research Institute) we have used bronchial brushings from healthy and asthmatic children to study the response of airway epithelial cells to challenge with respiratory viruses and allergens.
We have also begun a new set of studies to test the role of TSLP in the growth and metastasis of epithelial-derived tumors. Work from other groups found that these tumors (e.g., breast and lung) express TSLP and that the level of expression correlated with metastatic potential. We have generated a mouse model of metastatic breast cancer and have used it to show that TSLP is indeed critical for both tumor growth and metastasis. This work provides a new and novel approach for treating metastatic breast cancer, and work is underway in the lab on other tumor models. For example, we have found a role for IL-25 in colitis-associated cancer, a common feature of patients with inflammatory bowel disease. This work is now taking advantage of the BRI Translational Research Biorespository to examine the role of these cytokines in human cancers.