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 autoimmune diseases, e.g. type I diabetes.
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. DAP12-associated receptors, such as Ly49H and Ly49P, are involved in immunity against cytomegalovirus infection.
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 autoimmune diseases. |
Arase, H., E.S. Mocarski, A.E. Campbell, A.B. Hill, and L.L. Lanier. 2002. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296:1323-1326.
Ogasawara, K., J.A. Hamerman, H. Hsin, S. Chikuma, H. Bour-Jordon, T. Chen, T. Pertel, C. Carnaud, J.A. Bluestone and L.L. Lanier. 2003. Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity 18:41-51.
Rosen, D.B. M. Araki, J.A. Hamerman, T. Yamamura, and L.L. Lanier. 2004. A structural basis for the association of DAP12 with mouse, but not human, NKG2D. J. Immunol. 173:2470-2478.
Ogasawara, K., J.A. Hamerman, L.R. Ehrlich, H. Bour-Jordon, P. Santamaria, J.A. Bluestone, and L.L. Lanier. 2004. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 20:757-767.
Lodoen, M.B. and L.L. Lanier. 2005. Viral modulation of NK cell immunity. Nat. Rev. Microbiol. 3:59-69.
Lanier, L.L. 2005. NK cell recognition. Annu. Review Immunol. 23:225-274 .
Hamerman, J.A., N. K. Tchao, C.A. Lowell, and L.L. Lanier. 2005. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nature Immunology 6:579-586.
information last updated June 2005 |
Biomedical Sciences (BMS) Graduate Program
