Wayne M. Yokoyama, M.D.
Sam J. Levin and Audrey Loew Levin Professor
Pathology and Immunology
Howard Hughes Medical Institute
Molecular Microbiology and Microbial Pathogenesis Program
10058 Clinical Sciences Research Building
cancer, immunology, innate immunity, NK cells, tumor biology, virology
Host innate immune responses to pathogens and tumors
The innate immune system defends the host from pathogens and cancer while the adaptive immune system is being mustered. By providing early detection and control, it can also shape the T and B cell response. We study various aspects of the innate immune system in the context of murine cytomegalovirus (MCMV) and cowpox virus (CPXV) infections, as well as tumors.
Natural killer (NK) cells constitute a major constituent of the innate immune system. Interestingly, innate immune cells are often distinguished from adaptive immune cells by several features which include “memory,” a feature classically associated with adaptive but not innate immunity. Recently, however, we discovered that NK cells have memory-like properties that could be exploited to enhance immune responsiveness.
We are particularly interested in NK cell receptors that recognize ligands on their infected or tumor cell targets. Over the years, we have identified and characterized NK cell inhibitory receptors that recognize major histocompatibility complex class I molecules on the target cell. These inhibitory receptors block the function of NK cell activation receptors that recognize other target cell surface ligands, including molecules encoded by viruses. These receptors display profound allelic polymorphisms, as recently shown by our work with array-based comparative genomic hybridization.
Together, the NK cell receptors dictate whether or not the NK cell will kill normal or diseased cells. While this is related to their recognition of ligands on their cellular targets, it is also clear that they have other effects on NK cell function, i.e., tolerance, which also includes a recently described process termed “licensing” and “anergy” due to engagement of ligands expressed on self-tissues by the inhibitory receptor or activation receptor, respectively.
Our work on the role of NK cells in anti-pathogen defense has led to studies of innate immune responses to large DNA viruses, MCMV and CPXV. We are especially interested in how these viruses interact with the host, since much of their genomes is dispensable for in vitro growth and replication, i.e, they encode molecules that modulate the immune system. MCMV and CPXV are amenable for such analyses since their natural reservoirs are rodents and thus, immunopathogenesis studies in mice are applicable to host-pathogen interactions.
Choi T, Ferris ST, Matsumoto N, Poursine-Laurent J and Yokoyama WM. Ly49-dependent NK cell licensing and effector inhibition involve the same interaction site on MHC ligands. J Immunol 2011 186: 3911-3917. PMCID: PMC3082152
Paul WE, Littman DR and Yokoyama WM. (Eds.) Annual Review of Immunology Vol. 28, Annual Reviews, Inc. Palo Alto, 2010, 694 pp.
Elliott JM, Wahle JA and Yokoyama WM. MHC-class I-deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I-sufficient environment. J Exp Med 2010 207: 2073-2079. PMCID: PMC2947074
Higuchi DA, Cahan P, Gao J, Ferris ST, Poursine-Laurent J, Graubert TA and Yokoyama WM. Structural variation of the mouse natural killer gene complex. Genes and Immunity 2010 11: 637-648. PMCID: PMC2995812
Byun M, Verweij MC, Pickup DJ, Wiertz EJHJ, Hansen TH and Yokoyama WM. Two mechanistically distinct immune evasion proteins of cowpox virus combine to avoid antiviral CD8 T cells. Cell Host Microbe 2009 6:422-432. PMCID: PMC2791900
Jonsson AH and Yokoyama WM. Natural killer cell tolerance: Licensing and other mechanisms. Adv Immunol 2009 101:27-79.
Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, and Yokoyama WM. Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci (USA) 2009 106: 1915-1919. PMCID: PMC2644138
Tripathy SK, Keyel PA, Yang L, Pingel JT, Cheng TP, Schneeberger A, and Yokoyama WM. Continuous engagement of self-specific activation receptors induces NK cell tolerance. J Exp Med 2008 205: 1829-1841. PMCID: PMC2525593
Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song Y-J, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, and Yokoyama WM. Licensing of natural killer cells by host MHC class I. Nature 2005 436: 709-713.
Last Updated: 2/8/2012 8:20:19 AM