Dendritic cells (DCs) play an important role in initiating and maintaining adaptive immunity. However, the underlying mechanisms are not completely understood. Our research goal is to better understand the molecular mechanisms by which DCs shape and control T cell immunity.
The current research is focused on understanding the role of a membrane-anchored ubiquitin ligase named MARCH1 (Membrane-Associated RING-CH1). MARCH1 is highly expressed in dendritic cells, attaches ubiquitin chains to the cytoplasmic tail of MHCII, CD86, and possibly other membrane proteins, and mediates endocytosis, lysosomal sorting, and degradation of the substrates. Thus, MARCH1 is involved in surface turnover of specific immune-associated molecules in DCs. However, its functional role is not clearly understood.
The specific objectives are as following.
1. Determine the role of MARCH1 in DC function of establishing T cell tolerance. DCs play a significant role in establishing T cell tolerance through their ability to present self-antigens to developing T cells in the thymus. When antigen-presenting DCs make a cognitive interaction with antigen-specific thymocytes, this interaction leads the engaged thymocytes to apoptotic cell death or regulatory T cell differentiation. We are interested in determining whether MARCH1 is involved in any of these processes.
2. Determine the role of MARCH1 in DC function of driving T cell immunity. DCs play an essential role in the development of specific T cell immunity to various antigens. DC subset 1 drives cytotoxic T lymphocyte and T helper type 1 (Th1) immunity against virus, cancer, and intracellular bacteria or parasite whereas DC subset 2 drives Th17 immunity to fungi and extracellular bacteria and Th2 immunity to intestinal hookworm and allergens. We are interested in finding out whether MARCH1 plays an important role in the development and maintenance of any specific types of T cell immunity.
3. Determine the role of MARCH1 in T cell-dependent immune-stimulatory diseases. Many of immune-stimulatory diseases are associated with unregulated T cell immunity. Allergic diseases including allergic asthma are associated with strong Th2 immunity while certain autoimmune diseases such as multiple sclerosis are associated with strong Th1 and Th17 immunity. We are interested in determining whether MARCH1 is involved in the development and exacerbation of these T cell-dependent immune-stimulatory diseases and if so, whether MARCH1 could serve as a therapeutic target for treatment of these diseases.