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Ye Zheng

 

Ye Zheng

Ye Zheng

Assistant Professor
Emerald Foundation Developmental Chair
Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis

"The immune system must keep a delicate balance between effectively fighting foreign pathogens while minimizing collateral damage. Research in my lab is focused on generating and maintaining regulatory T cells, which prevent biological 'friendly fire' by ensuring that the immune system does not overly attack the body's own tissues."

The immune system is often described as a kind of military unit, a defense network that guards the body from intruders. Seen in this way, a group of white blood cells called T cells are the frontline soldiers of immune defense. The majority of T cells engage invading pathogens head on, while a smaller subset, called regulatory T cells, limit excessive immune reactions. Autoimmune diseases such as type 1 diabetes, Crohn's disease, lupus, and rheumatoid arthritis occur when the balance of power between the two breaks down.

Regulatory T cells are controlled by a pivotal gene regulator called Foxp3. In fact, when Foxp3 stops functioning, the body can no longer produce working regulatory T cells. Until now, however, scientists had barely understood what signals lead to Foxp3 expression and how Foxp3 in turn controls regulatory T cells because they knew very little about the actual genes under Foxp3's purview. Zheng identified several DNA elements in the Foxp3 locus that are directly involved in inducting and maintaining Foxp3 expression and that regulate the development and stability of regulatory T cell lineage. He then focused on the downstream targets of Foxp3. Using a genome-wide screen, Zheng mapped all genes directly regulated by Foxp3 and identified a small group of transcription factors–proteins that control the expression or "transcription" of genes–that drive the expression of genes involved in regulatory T cell function. One of them, IRF4, stood out as the key player in regulatory T cells' ability to control type-2 T helper cells, which, if uncontrolled, can activate other immune cells and lead to allergy and asthma.

In the future, Zheng will expand his current studies to determine how regulatory T cells are generated and maintained. His experiments not only will provide a better understanding of regulatory T cells but will suggest new therapeutic approaches for treating a wide range of autoimmune diseases, improving organ transplant survival, and boosting the immune system's response to tumors."

Lab Photo

Left to right:
Nina Miller, Ye Zheng, Oren Milstein

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Ye Zheng

Faculty

Ye Zheng

Ye Zheng

Assistant Professor
Emerald Foundation Developmental Chair
Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis

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.

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