Huang Laboratory
Our Lab Studies the Signaling and Transcriptional Regulation of Allergic Immune Responses and T Helper Cell Differentiation
CD4+ T helper cells (Th) and innate Th2-type cells are of critical importance in health and in disease. Three major types of Th subsets have been described-they are Th1, Th2 and Th17 subsets. Each subset can confer immune protection and cause tissue injury in the hosts. Generation of allergic immune responses require two types of effector cells: CD4+ Th2 cells and bone marrow-derived allergic effector cells, such as mast cells, eosinophils, and basophils. Both CD4+ Th cells and innate Th2-type cells are rich sources of cytokines that exert effector functions or play regulatory roles. Recent evidence indicates that basophils, in addition to acting as effector cells, can function as immune regulator cells. Our lab focuses on the signaling and transcriptional regulation of allergic cytokine gene expression.
Differentiation of allergic effector cells from bone marrow progenitors
Basophils have been linked to allergic diseases because they have been found at the site of allergic inflammation. These cells are potent allergic effector cells. Recent work has implied important roles for basophils in initiating and augmenting Th2-type immune responses to allergen challenges. Molecules, including IL-4, IL-6, and TSLP, have been demonstrated to be essential in mediating these novel basophil functions. However, due to the difficulty of obtaining sufficient numbers of basophils, how these key molecules are regulated at the molecular level is not understood. We have established an in vivo method to rapidly and specifically expand basophils, which allows us to study gene regulation of many novel basophil-mediated functions, such as initiating Th2 responses and enhancing B cell memory responses at the molecular level.
Based on our previous finding that IL-5 functions as a potent factor that drives bone marrow progenitor cells to differentiate into Th2 cytokine-producing eosinophils, we propose that IL-5 drives bone marrow progenitor cells primarily to differentiate into robust IL-4-producing eosinophils dependent upon signaling transducer activator of transcription 5 (STAT5) and transcription factor GATA1. We have demonstrated that STAT5 is essential to IL-5-induced Il4 gene expression in eosinophils. More recently, we have shown that GATA1 is also required for IL-5-induced Il4 gene expression in eosinophils. Currently, we are using GATA1 mutants to determine how GATA1 regulates the Il4 gene.
Interaction between Th2 cells and bone marrow progenitor cells
Th immunity, once established, can recuit a variety of bone marrow-derived allergic effector cells, such as eosinophils, basophils, and mast cells. However, it is less clear whether Th2 cells can interact with bone marrow progenitors cells that are precusors to those bone marrow-derived allergic effector cells and influence their differentiation in vivo. In this project, we adoptively transfer wild-type or mutant Th2 cells to naïve bone marrow chimera mice, which either house an overexpressed gene of interest or lack a gene of interest, to analyze the interaction between Th2 cells and bone marrow progenitor.
T helper cell differentiation
Despite a great deal of how Th2 cells is differentiated in vitro has been learned, little is known how Th2 immune responses are initiated in vivo. We focus on how Th2 immune responses are initiated in vivo in response to allergen challenge.
A critical balance between the Th1 and Th2 immune responses can be achieved through positive and negative regulations. Despite remarkable progress made toward understanding the positive regulations that drive naïve CD4+ T cells to differentiate into IL-4-producing cells, little is known about the negative regulations that silence Th2 cytokine gene transcription. This project focuses on the role of IFN-? and IL-27, a cytokine produced by dentritic cell, in silencing the Il4 gene. We are also expanding our efforts to search for novel Th2 inhibitory molecules, both human and mouse, and to understand how the novel Th2 inbitory molecules suppress Il4 gene transcription. Other projects include understanding the regulation of the Il17 gene, a gene that has been shown to be critical in many autoimmune diseases.
