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. |
Cerwenka, A., A.B.H. Bakker, T. McClanahan, J. Wagner, J. Wu, J.H. Phillips, and L.L. Lanier. 2000. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12:721-727.
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.
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.
Ogasawara, K., J. Benjamin, R. Takaki, J.H. Phillips, and L.L. Lanier. 2005. Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nature Immunology 6:938-945.
Carr, W.H., D.B. Rosen, H. Arase, D.F. Nixon, J. Michaelsson, and L.L. Lanier. 2007. Cutting Edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation. J. Immunol. 178:647-651.
Lanier, L.L. 2008. Evolutionary struggles between NK cells and viruses. Nature Reviews Immunology 8:259-268.
Rosen, D.B., W. Cao, D.T. Avery, S.G. Tangye, Y-J. Liu, J.P. Houchins, and L.L. Lanier. 2008. Expression and function of LLT1, a ligand of human NKR-P1A, on activated B cells and dendritic cells. J. Immunol. 180:6508-6517.
Lanier, L.L. 2008. Up on the tightrope - NK cell activation and inhibition. Nature Immunology 9:495-502.
Sun, J.C. and L.L. Lanier. 2008. Tolerance of NK cells encountering their viral ligand during development. J. Exp. Med. 205:1819-1828.
Sun, J.C. and L.L. Lanier. 2008. Cutting Edge: Viral infection breaks NK cell tolerance to "Missing Self". J. Immunol. 181:7453-7457.
Orr, M.T., J.C. Sun, D.G.T Hesslein, H. Arase, J.H. Phillips, T. Takai, and L.L. Lanier. 2009. Ly49H signaling through both DAP10 and DAP12 is required for optimal NK cell responses to mouse cytomegalovirus infection. J. Exp. Med. 206:807-817.
Sun, J.C., J.N. Beilke, and L.L. Lanier. 2009. Adaptive immune features of Natural Killer cells. Nature 457:557-561.
information last updated June 2009 |
Biomedical Sciences (BMS) Graduate Program
