Wayne M. Yokoyama, M.D.
Professor
Department of Medicine
Department of Pathology
Office: 10058 Clinical Sciences Research Building
Laboratory: 10002/10060/10062 Clinical Sciences Research Building

Office Phone: 314-362-9075
Fax: 314-362-9257
e-mail: yokoyama@imgate.wustl.edu

 
Natural killer (NK) cells are well known for their ability to kill certain tumors. However, it is now appreciated that NK cells have a significant role in host defense against invading pathogens, particularly intracellular organisms, and are capable of influencing the specific, acquired immune response. Also, recent studies have implicated these cells in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis and vasculitis.

Our laboratory is currently interested in the identification and characterization of cell surface receptors that guide the function of NK cells. We aim to find the molecules that determine whether an NK cell is activated to kill a tumor cell or produce hormone-like proteins, termed cytokines, that resist infections. Implicit in our search is to determine to what NK cell receptors bind. As these characterizations progress, we will be able to use molecular tools to precisely determine the role of NK cells in normal and deranged immunity, such as infections, rheumatoid arthritis, vasculitis, and cancer. The ultimate goal of our work is to elucidate the function of NK cells in normal and abnormal immune responses and to derive targeted therapeutic interventions that influence these innate effector cells.

NKC Repository

 

1.    Matsumoto, N., Mitsuki, M., Tajima, K., Yokoyama, W.M., and Yamamoto, K.  The functional binding site for the C-type lectin-like NK cell receptor Ly49A spans three domains of its MHC class I ligand.  J Exp Med  2001; 193:147-157.

2.    Plougastel, B., Dubbelde, C., and Yokoyama, W.M.  Cloning of Clr, a new family of lectin-like genes localized between mouse Nkrp1a and Cd69.  Immunogenetics  2001; 53:209-214.

3.    Matsumoto, Y., Wang, L.L., Yokoyama, W.M., and Aso, T.  Uterine macrophages express the gp49B inhibitory receptor in midgestation.  J Immunol  2001; 166:781-786.

4.    Mehta, I.K., Smith, H.R.C., Wang, J., Margulies, D.H., and Yokoyama, W.M.  A “chimeric” C57L-derived Ly49 inhibitory receptor resembling the Ly49D activation receptor.  Cell Immunol  2001; 209:29-41.

 5.    Matsumoto, N., Yokoyama, W.M., Kojima, S., and Yamamoto, K.  The NK cell MHC class I receptor Ly49A detects mutations on H-2Dd inside and outside of the peptide binding groove.  J Immunol  2001; 166:4422-4428.

 6.    Mehta, I.M., Wang, J., Roland, J., Margulies, D.H., and Yokoyama, W.M.  Ly49A allelic variation and MHC class I specificity.  Immunogenetics  2001; 53:572-583.

 7.    Martin, S.M., Mehta, I.K., Yokoyama, W.M., Thomas, M.L., and Lorenz, R.G.  Development of intestinal intraepithelial lymphocytes, natural killer cells, and natural killer 1.1+ T cells in CD45 deficient mice.  J Immunol  2001; 166:6066-6073.

8.    Plougastel, B.F.M., Matsumoto, K., Dubbelde, C., and Yokoyama, W.M.  Analysis of a 1 megabase BAC contig overlapping the mouse Nkrp1 cluster of genes:  Cloning of three new Nkrp1 members, Nkrp1d, Nkrp1e, and Nkrp1f.  Immunogenetics  2001; 53:592-598.

9.    Blazar, B.R., Lindberg, F.P., Ingulli, E., Panoskaltsis-Mortari, A., Oldenborg, P.-A., Iizuka, K., Yokoyama, W.M., and Taylor, P.A.  CD47 (integrin-associated protein) engagement of dendritic cell and macrophage counterreceptors is required to prevent the clearance of donor lymphohematopoietic cells.  J Exp Med  2001; 194:541-549.

10.  Brown, M.G., Dokun, A.O., Heusel, J.W., Smith, H.R.C., Beckman, D.L., Blattenberger, E.A., Dubbelde, C.E., Stone, L.R., Scalzo, A.A., and Yokoyama, W.M.  Vital involvement of a natural killer cell activation receptor in resistance to viral infection.  Science  2001; 292:934-937.

11.  Dokun, A.O., Kim, S., Smith, H.R.C., Kang, H.-S.P., Chu, D.T., and Yokoyama, W.M.  Specific and non-specific NK cell activation during virus infection.  Nature Immunol 2001; 2:951-956.

12.   Brown, M.G., Scalzo, A.A., Stone, L.R., Clark, P.Y., Du, Y., Palanca, B., and Yokoyama, W.M.  Nkc allelic variability among inbred mouse strains:  Evidence for Nkc haplotypes.  Immunogenetics  2001; 53:584-591.

13.   Dokun, A.O., Chu, D.T., Yang, L., Bendelac, A.S., and Yokoyama, W.M.  Analysis of in situ NK cell responses during viral infection.  J Immunol  2001; 167:5286-5293.

14.  Carayannopoulos, L.N., Naidenko, O.V., Kinder, J., Ho, E.L., Fremont, D.H., and Yokoyama, W.M.  Ligands for murine NKG2D display heterogeneous binding behavior.  Eur J Immunol  2002; 32:597-605.

15.  Kim, S., Iizuka, K., Kang, H.-S.P., Dokun, A., French, A.R., Greco, S., and Yokoyama, W.M.  In vivo developmental stages in murine natural killer cell maturation.  Nature Immunol  2002, 3:523-528.

16.  Furukawa, H., Iizuka, K., Poursine-Laurent, J., Shastri, N., and Yokoyama, W.M.  A ligand for the murine NK activation receptor Ly49D:  Activation of tolerized NK cells from b2-microglobulin-deficient mice.  J Immunol  2002; 169:126-136.

17.  Smith, H.R.C., Heusel, J.W., Mehta, I.K., Kim, S., Dorner, B.G., Naidenko, O.V., Iizuka, K., Furukawa, H., Beckman, D.L., Pingel, J.T., Scalzo, A.A., Fremont, D.H., and Yokoyama, W.M.  Recognition of a virus-encoded ligand by a natural killer cell activation receptor.  Proc Natl Acad Sci (USA)  2002; 99:8826-8831.

18.  Ho, E.L., Carayannopoulos, L.N., Poursine-Laurent, J., Kinder, J., Plougastel, B., Smith, H.R.C., and Yokoyama, W.M.  Costimulation of multiple NK cell activation receptors by NKG2D.  J Immunol  2002; 169:3667-3675.

19.  Carayannopoulos, L.N., Naidenko, O.V., Fremont, D.H., and Yokoyama, W.M.  Cutting Edge:  Murine UL16 binding protein-like transcript 1:  A newly described transcript encoding a high affinity ligand for murine NKG2D.  J Immunol  2002; 169:4079-4083.

20.  Gilfillan, S., Ho, E.L., Cella, M., Yokoyama, W.M., and Colonna, M.  NKG2D recruits two distinct adapters to trigger natural killer cell activation and costimulation.  Nature Immunol  2002; 3:1150-1155.

21.  Kaifu, T., Nakahara, J., Mishima, K. Kaji, M., Inui, M., Ujike, A., Tan-Takeuchi, K., Iwasaki, K., Yokoyama, W.M., Fujiwara, M., Asou, H., and Takai, T.  Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice.  J Clin Invest  2003; 111:323-332.

22.  Andrews, D.M., Scalzo, A.A., Yokoyama, W.M., Smyth, M.J., and Degli-Esposti, M.A.  Functional interactions between dendritic cells and NK cells during viral infection.  Nature Immunol  2003; 4:175-181.

23.  Backström, E., Chambers, B.J., Ho, E.L., Naidenko, O.V., Mariotti, R., Fremont, D.H., Yokoyama, W.M., Kristensson, K., and Ljunggren, H.-G.  Natural killer cell-mediated lysis of dorsal root ganglia neurons via RAE1/NKG2D interactions.  Eur J Immunol  2003; 33:92-100.

24.  Gu, X., Laouar, A., Wan, J., Daheshia, M., Lieberman, J., Yokoyama, W.M., Katz, H.R., and Manjunath, N.  The gp49B1 inhibitory receptor regulates the IFN-g responses of T cells and NK cells.  J Immunol  2003; 170:4095-4101.

25.  Iizuka, K., Naidenko, O.V., Plougastel, B.F.M., Fremont, D.H., and Yokoyama, W.M.  Genetically linked C-type lectin-related ligands for the Nkrp1 family of NK cell receptors.  Nature Immunol  2003; 4:801-807.

26.  Scalzo, A.A., Wheat, R., Dubbelde, C., Stone, L., Clark, P.,  Du, Y., Dong, N., Stoll, J., Yokoyama, W.M., and Brown, M.G.  Molecular genetic characterization of the distal NKC recombination hotspot and putative murine CMV resistance control locus.  Immunogenetics  2003; 55:370-378.

27.  Voigt, V., Forbes, C.A., Tonkin, J.N., Degli-Esposti, M.A., Smith, H.R.C., Yokoyama, W.M., and Scalzo, A.A.  Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells.  Proc Natl Acad Sci (USA)  2003; 100:13483-13488.

28.  Dorner, B.G., Smith, H.R.C., French, A.R., Kim, S., Poursine-Laurent, J., Beckman, D.L., Pingel, J.T., Kroczek, R.A., and Yokoyama, W.M.  Coordinate expression of cytokines and chemokines by natural killer cells during murine cytomegalovirus infection.  J Immunol  2004, 172:3119-3131.

29.  Whitman, S.C., Rateri, D.L., Szilvassy, S.J., Yokoyama, W., Daugherty, A.  Depletion of natural killer cell function decreases atherosclerosis in low-density lipoprotein receptor null mice.  Atheroscler Thromb Vasc Biol  2004;  24:1-7.

30.  French, A.R., Pingel, J.T., Wagner, M., Bubic, I., Yang, L., Kim, S., Koszinowski, U., Jonjic, S., and Yokoyama, W.M.  Escape of mutant double-stranded DNA virus from innate immune control.  Immunity  2004; 20:747-756.

31.  Warfield, K.L., Perkins, J.G., Swenson, D.L., Deal, E.M., Bosio, C.M., Aman, M.J., Yokoyama, W.M., Young, H.A., and Bavari, S.  Role of natural killer cells in innate protection against lethal Ebola virus infection.  J Exp Med  2004; 200:169-179.

32.  Bubic, I., Wagner, M., Krmpotic, A., Saulig, T., Kim, S., Yokoyama, W.M., Jonjic, S., and Koszinowski, U.H.  Gain-of-virulence caused by loss of a gene in murine cytomegalovirus.  J Virol  2004; 78:7536-7544.

33.  Krug, A., French, A.R., Barchet, W., Fischer, J.A.A., Dzionek, A., Pingel, J.T., Orihuela, M., Akira, S., Yokoyama, W.M., and Colonna, M.  TLR9-dependent recognition of murine cytomegalovirus (MCMV) by interferon-producing cells and dendritic cells generates a coordinated cytokine response that activates anti-viral NK cell function.  Immunity  2004; 21:107-119.


Invited  Publiciations

1.    Wang, L.L. and Yokoyama, W.M.  Regulated expression of non-polymorphic gp49 molecules on murine natural killer cells.  In Activating and Inhibitory Immunoglobulin-Like Receptors (Cooper, M.D., Takai, T., Ravetch, J.V., Eds.)  Tokyo:  Springer-Verlag, 2001; p. 17-31.

2.    Smith, H.R.C., Idris, A.H., and Yokoyama, W.M.  Murine natural killer cell activation receptors.  Immunol Rev  2001; 181:115-125.

3.    Matsumoto, N., Mitsuki, M., Tajima, K., Yokoyama, W.M., and Yamamoto, K.  Identification of the functional recognition site on MHC class I for an NK cell lectin-like receptor. In Activating and Inhibitory Immunoglobulin-Like Receptors (Cooper, M.D., Takai, T., Ravetch, J.V., Eds.)  Tokyo:  Springer-Verlag, 2001; p. 215-223.

4.    Yokoyama, W.M.  Natural killer cells in innate immunity to infection.  In Innate Immunity (Ezekowitz, R.A.B.,and Hoffmann, J., Eds.).  Totowa, NJ:  Humana Press, 2002; pg 321-339.

5.    Siva, C., Yokoyama, W.M., McLeod, H.L.  Pharmacogenetics in rheumatology:  The prospects and limitations of an emerging field.  Rheumatology  2002; 41:1273-1279.

6.    Yokoyama, W.M.  The search for the missing “missing-self” receptor on natural killer cells.  Scand J Immunol  2002; 55:233-237.  (Novartis Award lecture.)

7.    Yokoyama, W.M., and Scalzo, A.A.  Natural killer cell activation receptors in innate immunity to infection.  Microbes and Infection  2002; 15:1513-1521.

8.    Yokoyama, W.M.  News and views:  Immunology:  Catch us if you can.  Nature 2002; 419:679-680.

9.    Ranganathan, P., Eisen, S., Yokoyama, W.M., and McLeod, H.L.  Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis?  Ann Rheum Dis  2003; 62:4-9.

10.   French, A.R., and Yokoyama, W.M.  Natural killer cells and viral infection.  Curr Opin Immunol  2003; 15:45-51.

11.   Yokoyama, W.M., and Plougastel, B.F.M.  Immune functions
         encoded by the natural killer gene complex.  Nature Rev
         Immunol
  2003; 3:304-316.

12.  Yokoyama, W.M.  Innate natural killer cell responses to infection.  In The Innate Immune Response to Infection (Kaufmann, S.E., Medzhitov, R., and Gordon, S., Eds.)  Philadelphia, PA:  American Society for Microbiology Press, 2004; gp 133-155.

13.  Yokoyama, W.M., Kim, S., and French, A.R.  The dynamic life of natural killer cells.  Ann Rev Immunol, 2004; 22:405-429.

14.  Carayannopoulos, L.N., and Yokoyama, W.M.  Recognition of
       infected cells by natural killer cells.  Curr Opin Immunol 2004;       
       16:26-33.

15.  French, A.R., and Yokoyama, W.M.  Natural killer cells and autoimmunity.  Arthritis Res Ther  2004; 6:8-14.

16.  Yokoyama, W.M.  Betting on NKT and NK cells.  Immunity  2004; 20:363-365.

17.  Liszewski, M.K., Yokoyama, W.M., and Atkinson, J.P.  II:
       Innate Immunity.  6 Immunology/Allergy.  In ACP Medicine Online
       (Dale, D.C., Federmann, D.D., Eds.), New York:  WebMD
        Inc., 2004.