Our laboratory is working on two major projects to better understand the immune regulatory mechanisms.
1) Understanding ICOS function in helper T cell immunityICOS (inducible costimulator) is a member of CD28 family expressed in activated/antigen-experienced T cells. Its crucial role in the regulation of antibody generation is highlighted in human diseases; loss of ICOS gene causes CVID (common variable immunodeficiency) whereas an overt expansion of ICOS+ T cells is associated with rheumatoid arthritis. It is known that ICOS-mediated costimulation is crucial for differentiation and/or function of “helper T cells” that facilitate B cells to make high affinity antibodies. However, how ICOS exerts its impact is largely unknown. We recently demonstrated that ICOS activates the lipid kinase phosphatidylinositide 3’ kinase (PI3K) to promote the generation and possibly function of helper T cells (see Model). Our future research goals include: i) detailed mapping of ICOS signal transduction pathways, ii) evaluating the role of the signaling components in overall humoral immunity against protein antigens, viruses, and autoantigens.
2) B7 family proteins in cancer immune evasionIt is becoming clear that there is an ongoing battle between cancerous cells and the immune system and malignant tumors are under the selection pressure to develope ways to evade the immune attack. Thus, blocking the immune evasion mechanisms utilized by developing tumors represents an opportunity to control cancer. Members of the inhibitory B7 family proteins such as B7-H3, B7-H4, and PD-L1, are often overexpressed on various human cancer cells raising the possibility that these proteins provide growth advantage to cancer in the face of T cell immunity. We are currently testing this idea using mouse models genetically predisposed to develop tumors.