Lewis Lanier, PhD

Regulation of T Cell and NK Cell Immune Responses by Activting and Inhibitory Receptors

Professor and Vice-Chair, Department of Microbiology and Immunology
Professor, Cancer Research Center
513 Parnassus, HSE 1001D, Box 0414
San Francisco, CA 94143-0414

(415) 514-0829 tel
(415) 502-8424
lewis.lanier@ucsf.edu
Lab website

AA: Stephanie Louie

Description of Research

NK cell receptors in viral immunity, tumor immunity, and autoimmunity.

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.

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 NKGD2 receptor in mice. Immunity 12:721-7727.

Ravetch, J.V. and L.L. Lanier. 2000. Immune inhibitory receptors. Science 290:84-89.

Cerwenka, A., and L.L. Lanier. 2001. NK cells, viruses and cancer. Nat. Rev. Immunol. 1:41-49.

Cerwenka A, Baron JL, and L.L. Lanier. 2001. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits NK cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc. Natl. Acad. Sci. USA 98:11521-11526.

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.

Lodoen, M., K. Ogasawara, J.A. Hamerman, H. Arase, J.P. Houchins, E.S. Mocarski, and L.L. Lanier. 2003. NKG2D-mediated NK cell protection against cytomegalovirus is impaired by gp40 modulation of RAE-1 molecules. J. Exp. Med. 197:1245-1253.

Ogasawara, K., J.A. Hamerman, H. Hsin, S. Chikuma, H. 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.

L.L. Lanier. 2003. Natural killer cell receptor signaling. Curr. Opin. Immunol. 15:308-314.

Wu, J., and L.L. Lanier. 2003. NK cells and cancer. Adv. Cancer Res. 90:128-156.

Hamerman, J., K. Ogasawara, and L.L. Lanier. 2004. Cutting Edge:Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J. Immunol. 172:2001-2005.

Rosen, D.B. M. Araki, J.A. Hamerman, T. Yamamura, andL.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, J.A. Bluestone, and L.L. Lanier. 2004. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 20:757-767.

Zingoni, A., T. Sornasse, B.G. Cocks, Y. Tanaka, A. Santoni, and L.L. Lanier. 2004. Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40L interactions. J. Immunol. 173:3716-3724. 

Lodoen, M.B., G. Abenes, S. Umamoto, J.P. Houchins, F. Liu, and L.L. Lanier. 2004. The cytomegalovirus m155 gene product subverts NK cell antiviral protection by disruption of H60-NKG2D interactions. J. Exp. Med. 200:1075-1081.

Lodoen, M.B. and L.L. Lanier. 2005. Viral modulation of NK cell immunity. Nat. Rev. Microbiol. 3:59-69.

Hamerman, J.A., K. Ogasawara, and L.L. Lanier. 2005. NK cells in innate immunity. Curr. Opin. Immunol. 17:29-35.

L.L. Lanier. 2005. NK cell recognition. Annu. Review Immunol. 23:225-274.

Ehrlich, L.R., K. Ogasawara, J.A. Hamerman, R. Takaki, A. Zingoni, J.P. Allison, and L.L. Lanier. 2005. Engagement of NKG2D by cognate ligand or antibody alone is insufficient to mediate costimulation of human and mouse CD8+ T cells. J. Immunol. 174:1922-1931.

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. Nat. Immunol. 6:579-586.

Takaki, R., Y. Hayakawa, A. Nelson, P.V. Sivakumar, S. Hughes, M.J. Smyth, and L.L. Lanier. 2005. IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. J. Immunol. 275:2167-2173.

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. Nat. Immunol. 6:938-945.

Rosen, D.B., J. Bettadapura, M. Alsharifi, P.A. Mathew, H.S. Warren, and L.L. Lanier. 2005. Cutting Edge:  Lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor.  J. Immunol. 175:7796-7799.

Hesslein, D.G.T., R. Takaki, M.L. Hermiston, A. Weiss, and L.L. Lanier. 2006.  Dysregulation of signaling pathways in CD45-deficient NK cells leads to differentially regulated cytotoxicity and cytokine production. Proc. Natl. Acad. Sci. USA 103:7012-7017.

Hamerman, J.A., J.R. Jarjoura, M.B. Humphrey, M.C. Nakamura, W.E. Seaman, and L.L. Lanier. 2006. Cutting Edge: Inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM-2) and DAP12. J. Immunol. 174:2051-2055.

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.

Adams, E.J., Z.S. Juo, R.T. Venook, M.J. Boulanger, H. Arase, L.L. Lanier, and K.C. Garcia. 2007. Structural elucidation of m157, a mouse cytomegalovirus, MHC-like ligand for natural killer cell Ly49 receptors. Proc. Natl. Acad. Sci. USA 104:10128-10133.