Yongqiang Feng Lab

Immune tolerance is a finely tuned state of immune unresponsiveness that prevents the immune system from mistakenly attacking the body’s own tissues, food and commensal microbiome. This process is essential for preventing autoimmune diseases and allergies as well as maintaining immune balance. Regulatory T (Treg) cells are long-lived suppressor T cells that play a crucial role in immune tolerance and homeostasis throughout life. Our research bridges basic immunology and preclinical models to uncover how immune suppressive Treg cells interact with inflammatory T cells and tissue cells. We also explore how Treg cells can be harnessed or reprogrammed to treat autoimmune diseases, cancer, and chronic inflammation.

We employ cutting-edge technologies, such as novel preclinical models, genome editing, structure-guided protein design, single-cell multiomics and computational analysis to investigate how Treg cells are programmed by environmental and genetic factors through signaling pathways, epigenetic modifications and transcriptional regulation. These processes establish and maintain immunosuppressive memory toward self-antigens, foreign antigens and neoantigens. Conversely, we study how disruptions in these processes lead to immune-related diseases or how tumors exploit them to evade immune attack. We also leverage this knowledge to explore the therapeutic potential of Treg cells through synthetic biology approaches.

Treg lineage stability and long-term tolerance

Treg cells are long-lived, but how their lineage stability is maintained remains a key research question. Investigating regulation of the Treg master regulator, Foxp3, provides a simple yet powerful approach to address this question. Specific DNA regions act like switches to keep Foxp3 active. If these switches fail, Treg cells lose their identity and stability, leading to widespread inflammation. Our lab is exploring how these mechanisms operate in health and disease, and how we might modulate them to enhance or reduce Treg stability for therapeutic benefit.

Treg diversity and suppression strategies

Treg cells are induced in the thymus or peripheral tissues in response to self-antigens or foreign antigens presented by specialized antigen-presenting cells (APCs), such as medullary thymic epithelial cells (mTECs). This tolerance memory is established during the initial encounter with these antigens and is crucial for selectively suppressing T-cell reactivity towards specific targets, including self-organs, food antigens and the commensal microbiome.

Treg induction involves a complex interplay between specialized APCs and Treg precursors through both extrinsic and intrinsic mechanisms. Our studies show that Treg development is guided by key genetic programs that shape their specificity and function. Disruption of these programs can lead to outcomes ranging from mild immune dysregulation to fatal systemic autoimmunity. Our work provides insights into how Treg cells adapt to different targets and how their suppression strategies shift.

Gene regulation in T-cell tolerance

We are also exploring how immune tolerance is established through gene regulation in both Treg cells and conventional T cells. Using cutting-edge epigenetic and proteomics tools, we discovered that Foxp3 does not function as a typical transcription factor but rather as a transcriptional cofactor. This seemingly minor reclassification of Foxp3 leads to a profoundly different comprehension of how it regulates gene expression to determine the fate and function of Treg cells.

We are investigating the association of Foxp3 with other DNA-binding proteins, such as NFAT, to address the nature of Foxp3-DNA and Foxp3-chromatin interactions. We are also elucidating the key determinants of dynamic Foxp3-dependent gene regulation and the immunological contexts that rely on these mechanisms