1) Regulation of T cell responses
T cells are pivotal players in the immune response. They are beneficial in combating infections and cancer but can also be harmful in autoimmunity and immunopathologic states. T cell activation is primarily initiated by intracellular signals emanating through their T cell receptor. These signals can be further modified by engagement of other cell surface receptors and by negative regulators of signaling. Currently, we study the role of the NK cell receptor NKG2D in controlling T cell activation. In addition, we are investigating the roles of negative regulators of calcium and daicylglycerol signaling in T cell activation and differentiation.
2) Regulatory T cell expansion and homeostasis
In addition to the cell-intrinsic regulation of T cell activation as described above, T cells are controlled cell extrinsically by regulatory T cells. Regulatory T cells represent a subset of CD4+ T cells that possess the ability to suppress the activation and expansion of other conventional CD4+ T cells. They are distinguished from conventional T cells by constitutive expression of CD25 and the transcription factor Foxp3. The importance of regulatory T cells is evidenced by the severe autoimmunity that develops in mice and humans lacking regulatory T cells. We are actively investigating how signal transduction processes affect the development, homeostasis, expansion, and function of regulatory T cells. We translate our findings to therapeutic approaches in the prevention of inflammatory diseases such as multiple sclerosis, graft-versus-host disease, diabetes, rheumatoid arthritis, and inflammatory bowel disease.
4) NK cell education and signaling
NK cells are innate immune cells that provide a critical line of defense against intracellular pathogens and tumors by displaying cytotoxicity and producing immune-activating cytokines. One key mechanism that regulates their activation involves the expression of activating receptors that are finely counterbalanced by inhibitory MHC class I-binding receptors. Thus, the interaction of NK cells with abnormal cells that have decreased MHC class I expression relieves the inhibition conferred by the MHC-binding inhibitory receptors, leading to activation and cytotoxicity by the NK cell. NK cells heterogeneously express one or more of the many inhibitory receptors, which are acquired by NK cells during later stages of their development. The heterogeneity of NK cell receptor expression allows NK cells to discriminate between cells expressing normal and abnormal amounts of various MHC class I molecules. As the signaling requirements of these receptors during development and effector function remain unclear, we have been investigating the signal transduction pathways during NK cell activation. In doing so, we have identified some key signaling molecules that are necessary for proper acquisition of MHC-binding inhibitory receptors during development. We are further investigating the molecular mechanisms that are responsible for regulating inhibitory receptor acquisition during NK cell development and how it relates to the functional outcome of the NK cell response.