Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis
Hearst Foundation Developmental Chair
Regulatory T cells (Treg) are a specialized subset of T cells that play a critical role in suppression of over-exuberant immune response and maintenance of immune system homeostasis. Abnormal Treg function has been linked to multiple autoimmune diseases, such as arthritis, type-1 diabetes, lupus, and multiple sclerosis, as well as inefficient tumor immunity.
Research in my lab is focused on the molecular and cellular mechanisms of regulatory T cell development and function. Using chromatin immunoprecipitation (ChIP) coupled with whole genome tiling array, we mapped ~700 genes that are directly regulated by Foxp3, a member of the forkhead transcription factor family that is expressed specifically in regulatory T cells. It plays a pivotal role in Treg development and function, while mutations of Foxp3 in human and mice lead to deficiency of regulatory T cells and fatal autoimmune disease.
Among the Foxp3 direct targets, there is a small group of transcription factors that potentially facilitate Foxp3 dependent suppressor programs in a modular fashion. For instance, IRF4 is required for suppression of Th2 immune response associated with asthma and allergy, and STAT3 is indispensible for suppression of Th17 response associated with inflammatory bowel disease (IBD). Our current goal is to further elucidate the Foxp3 transcriptional network, and shed more light on the molecular mechanisms of regulatory T cell suppressor function.
Since Foxp3 is the defining factor for regulatory T cells, the mechanism that regulates the induction and maintenance of Foxp3 expression also determines the development and stability of Treg cell lineage. To this end, we used a bottom-up approach to study pathways that regulate Foxp3 expression. By comparing Foxp3 genomic sequences among different species, we identified three conserved non-coding sequences (CNS) in the intronic region of the Foxp3 gene. Mice harboring deletion of individual CNS were generated to study the functions of these CNS regions in vivo. We showed each CNS has a distinct non-redundant function in Treg fate determination. Following up the initial characterization, we will further dissect the upstream pathways that control the expression of Foxp3 and regulatory T cell homeostasis.
The long-term goal of my lab is to search for novel ways to enhance or attenuate Treg activity, and to apply our findings in treatment of autoimmune diseases, improvement of organ transplant survival, and augmentation of anti-tumor immunity.
The immune system is a powerful doubleedged sword. On one hand, it is armed to fight a wide range of invading foreign pathogens. On the other hand, if left unchecked, it can also attack an organism's own tissues and cause autoimmune diseases, such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis. There are multiple safeguard mechanisms built into our immune system to prevent an autoimmune reaction. A subset of T cells, named regulatory T cells (Tregs), plays a key role in maintaining immune homeostasis.
Abnormal Treg function has been linked to a number of autoimmune diseases. Recent studies showed that a protein known as Foxp3 is a pivotal regulator for Treg differentiation and function. Mutations of Foxp3 in humans and mice lead to a deficiency of regulatory T cells and fatal autoimmune disease. Zheng's lab is interested in mapping both the upstream pathways that turn on Foxp3 expression and the downstream genes that Foxp3 regulates. Zheng and his colleagues identified several genes in the area of DNA that codes for Foxp3 and are found in a number of mammalian species. These genes appear to be involved in controlling and maintaining Foxp3 activity and in regulating the development and stability of regulatory T cell lineage. Using genomic approaches, the researchers were able to map all Foxp3 downstream target genes. They showed that among all Foxp3 targets, a small group of proteins is implicated in Treg-mediated suppression of different subtypes of autoimmune responses.
Zheng and his team are now further exploring the Foxp3 transcriptional network in regulatory T cells and searching for key molecules involved in the Treg suppression function. Since manipulations of Tregs can either weaken or strengthen the immune response, their findings can potentially open new avenues in the treatment of autoimmune diseases, improve organ transplant survival and enhance anti-tumor immunity."