Immune responses are regulated by membrane receptors that serve to activate or inhibit cell proliferation and clonal expansion, cytokines production, and cell-mediated cytotoxicity. Our lab focuses on the human and mouse activating and inhibitory receptors that are predominantly expressed by Natural Killer (NK) cells, but are also present on subsets of effector/memory T cells and some myeloid cells. We are particularly interested in the activating NK receptors that signal by associating with two distinct signaling adapter proteins named DAP10 and DAP12.
The DAP10 signaling adapter associates with the NKG2D receptor on NK cells and T cells, and DAP10 initiates signaling through the PI3-kinase pathway. We have implicated the NKG2D-DAP10 receptor in NK cell and T cell-mediated immune responses against certain tumors and viruses, but also demonstrated a detrimental role of this receptor in the rejection of allogeneic tissues. For example, NK cells mediate the rejection of allogeneic hematopoietic stem cells and participate in the rejection of heart allografts.
The DAP12 signaling adapter associates with many different human and mouse receptors, including activating KIR, Ly49, CD94/NKG2C, and several myeloid receptors. Like the CD3 subunits of the T cell antigen receptor, DAP12 has an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. When a DAP12-associated receptor encounters its ligand, DAP12 is tyrosine phosphorylated, which results in the recruitment and activation of the tyrosine kinases ZAP70 or syk - initiating cytokine production and cell-mediated cytotoxicity. NK cells expressing DAP12-associated Ly49D receptors have been shown to cause rejection of allogeneic hematopoietic stem cells.
The goal of our research is to understand the role of these NK cell receptors in immune defense against tumors and microbial pathogens, and explore their potential detrimental role in transplantation. NK cells may be an important barrier to the therapeutic use of stem cells, if the transplanted stem cells are not derived from the same individual.