About

Dr. Fumio Takei,  PhD
Senior Scientist

• Professor, Pathology & Laboratory Medicine, University of British Columbia (UBC)
• Associate Member, Medical Genetics, University of British Columbia (UBC)
• Associate Member, Microbiology, University of British Columbia (UBC)

 

Research Interest

Natural killer (NK) cells have two major functions, namely killing of tumor cells and production of cytokines, in particular interferon-g. These functions of NK cells are triggered by cell surface receptors that recognize ligands on tumor cells or cytokines. NK cells also express inhibitory receptors that recognize MHC class I on normal cells. A balance between stimulatory and inhibitory receptors mediates anti-tumor NK cell functions and tolerance to normal cells. In our laboratory, we are studying how NK cells acquire those stimulatory and inhibitory receptors as well as their functions during their development and how the process of tumor cell killing is regulated. These studies will likely lead to new ways to enhance anti-tumor functions of NK cells without affecting self-tolerance.

It is generally thought that NK cells develop from hematopoietic stem cells in the bone marrow and migrate to various tissues. However, we have recently found NK cell progenitors in the lymph node and lung and suggested the presence of multiple pathways of NK cell development, which may explain why NK cells in various tissues differ from each other in phenotype and function. We are currently studying the relationship between the NK cell progenitors we have identified and other lymphoid progenitors. We are also investigating the mechanisms by which NK cells acquire their functions during development.

Killing of tumor cells by NK cells is a multi-step process, namely initial binding to target, subsequent polarization of NK cells and finally polarization and exocytosis of lytic granules. We have shown that the cell adhesion molecule LFA-1 not only mediates binding of NK cells to target cells but also acts as a stimulatory receptor and induces actin polarization in NK cell. By studying NK cells generated in vitro from mutant ES cells, we have shown that the cytoplasmic protein talin is critical for LFA-1-mediated actin polarization. We are currently studying the mechanisms that regulate polarization of lytic granules, how inhibitory receptors inhibit the killing process and why the process is impaired in NK cells that develop in MHC class I-deficient mice.

NK cells stimulated by cytokines such as IL-12 and IL-18 or toll-like receptor ligands such as CpG-oligodeoxynucleotides produce large amounts of interferon-g. We have recently found that B cells unexpectedly regulate the stimulation of NK cells by IL-12 and CpG-oligodeoxynucleotides. As they are often used as adjuvant to enhance anti-tumor immunity, we are currently exploring ways to enhance NK cell functions by controlling B cell-mediated regulatory mechanisms.

  

Publications

Selected Publications 

2010

Mace EM, Zhang J, Siminovitch KA & Takei F. Elucidation of the integrin FLA-1 mediated signaling pathway of actin polarization in natural killer cells.  Blood, 116: 1272-1279, 2010. View Abstract

 

2009

Alcon VL, Luther C, Balce D & Takei F. B cell co-receptor CD72 is expressed on NK cells and inhibits IFN-g production but not cytotoxicity.  Eur J Immunol 39: 826-832, 2009. View Abstract

Haddad EA, Senger LK & Takei F. An accessory role for B cells in the IL-12 induced activation of resting mouse NK cells.  J Immunol 183: 3608-3615, 2009. View Abstract

Mace E, Monkley SJ, Critchley DR & Takei F. A dual role for talin in NK cell cytotoxicity: acitviation of LFA-1 mediated cell adhesion and polarization of NK cells.  J Immunol 182: 948-956, 2009. View Abstract

2008

Veinotte LL, Halim TYF & Takei F. Unique subset of natural killer cells develops from progenitors in lymph node. Blood 111: 4201-4208, 2008. View Abstract

Mace EM, MacLeod MA, Marwali MZ, Dreolini L & Takei F. LFA-1 binding to ligand induces talin-mediated reorganization of the actin cytoskeleton in cytotoxic T cells.  Open Immunol J 1: 51-61, 2008.

2007

Wilson EB, Parachoniak CA, Carpenito C, Mager DL, & Takei F. Expression of murine killer immunoglobulin-like receptor KIRL1 on CD1d-independent NK1.1(+) T cells. Immunogenetics 59 (8): 641-51, 2007. View Abstract

Tabatabaei-Zavareh N, Vlasova A, Greenwood CP, & Takei F. Characterization of developmental pathway of natural killer cells from embryonic stem cells in vitro. PLoS ONE 2 (2): e232, 2007. View Abstract

2006

Veinotte LL, Greenwood CP, Mohammadi N, Parachoniak CA, & Takei F. Expression of rearranged TCRgamma genes in natural killer cells suggests a minor thymus-dependent pathway of lineage commitment. Blood 107 (7): 2673-9, 2006. View Abstract

2005

Maeda M, Carpenito C, Russell RC, Dasanjh J, Veinotte LL, Ohta H, Yamamura T, Tan R, & Takei F. Murine CD160, Ig-like receptor on NK cells and NKT cells, recognizes classical and nonclassical MHC class I and regulates NK cell activation. J Immunol 175 (7): 4426-32, 2005. View Abstract

2004

Marwali MR, MacLeod MA, Muzia DN, & Takei F. Lipid rafts mediate association of LFA-1 and CD3 and formation of the immunological synapse of CTL. J Immunol 173 (5): 2960-7, 2004. View Abstract

Maeda M, Shadeo A, MacFadyen AM, & Takei F. CD1d-independent NKT cells in beta 2-microglobulin-deficient mice have hybrid phenotype and function of NK and T cells. J Immunol 172 (10): 6115-22, 2004. View Abstract

2003

Marwali MR, Rey-Ladino J, Dreolini L, Shaw D, & Takei F. Membrane cholesterol regulates LFA-1 function and lipid raft heterogeneity. Blood 102 (1): 215-22, 2003. View Abstract

2002

Lian RH, Maeda M, Lohwasser S, Delcommenne M, Nakano T, Vance RE, Raulet DH, & Takei F. Orderly and nonstochastic acquisition of CD94/NKG2 receptors by developing NK cells derived from embryonic stem cells in vitro. J Immunol 168 (10): 4980-7, 2002.View Abstract

2001

Maeda M, Lohwasser S, Yamamura T, & Takei F. Regulation of NKT cells by Ly49: analysis of primary NKT cells and generation of NKT cell line. J Immunol 167 (8): 4180-6, 2001. View Abstract

Takei F, McQueen KL, Maeda M, Wilhelm BT, Lohwasser S, Lian RH, & Mager DL. Ly49 and CD94/NKG2: developmentally regulated expression and evolution. Immunol Rev 181: 90-103, 2001. View Abstract

2000

Williams NS, Kubota A, Bennett M, Kumar V, & Takei F. Clonal analysis of NK cell development from bone marrow progenitors in vitro: orderly acquisition of receptor gene expression. Eur J Immunol 30 (7): 2074-82, 2000. View Abstract

1999

Kubota A, Lian RH, Lohwasser S, Salcedo M, & Takei F. IFN-gamma production and cytotoxicity of IL-2-activated murine NK cells are differentially regulated by MHC class I molecules. J Immunol 163 (12): 6488-93, 1999. View Abstract

Kubota A, Kubota S, Lohwasser S, Mager DL, & Takei F. Diversity of NK cell receptor repertoire in adult and neonatal mice. J Immunol 163 (1): 212-6, 1999. View Abstract

Lian RH, Li Y, Kubota S, Mager DL, & Takei F. Recognition of class I MHC by NK receptor Ly-49C: identification of critical residues. J Immunol 162 (12): 7271-6, 1999. View Abstract

Rey-Ladino JA, Huber M, Liu L, Damen JE, Krystal G, & Takei F. The SH2-containing inositol-5’-phosphatase enhances LFA-1-mediated cell adhesion and defines two signaling pathways for LFA-1 activation. J Immunol 162 (10): 5792-9, 1999. View Abstract

1998

Rey-Ladino JA, Pyszniak AM, & Takei F. Dominant-negative effect of the lymphocyte function-associated antigen-1 beta (CD18) cytoplasmic domain on leukocyte adhesion to ICAM-1 and fibronectin. J Immunol 160 (7): 3494-501, 1998. View Abstract

1997

Takei F, Brennan J, & Mager DL. The Ly-49 family: genes, proteins and recognition of class I MHC. Immunol Rev 155: 67-77, 1997. View Abstract

1996

Brennan J, Lemieux S, Freeman JD, Mager DL, & Takei F. Heterogeneity among Ly-49C natural killer (NK) cells: characterization of highly related receptors with differing functions and expression patterns. J Exp Med 184 (6): 2085-90, 1996. View Abstract

Brennan J, Mahon G, Mager DL, Jefferies WA, & Takei F. Recognition of class I major histocompatibility complex molecules by Ly-49: specificities and domain interactions. J Exp Med 183 (4): 1553-9, 1996. View Abstract

1994

Brennan J, Mager D, Jefferies W, & Takei F. Expression of different members of the Ly-49 gene family defines distinct natural killer cell subsets and cell adhesion properties. J Exp Med 180 (6): 2287-95, 1994. View Abstract

1989

Horley KJ, Carpenito C, Baker B, & Takei F. Molecular cloning of murine intercellular adhesion molecule (ICAM-1). Embo J 8 (10): 2889-96, 1989. View Abstract

Lab People

Postdoctoral Fellow

Graduate Students Evette Haddad Tim Halim Laura Guillon (nee Senger) Valeria Rytova Kathrin Warner

Other members

Open Positions

April 2010: We are currently accepting post-doctoral applications.