Principal Investigators


Dr. Fumio Takei — PhD

Distinguished Scientist

Admin Contact

Christine Kelly

Senior Secretary
Research Interest
Lab Members
  • 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)


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.


Selected Publications


Matha L, Shim H, Steer CA, Yin YH, Martinez-Gonzalez I & Takei F. Female and male mouse lung group 2 innate lymphoid cells differ in gene expression profiles and cytokine production. PLoS One 14: e0214286, 2019. View Abstract

Romera-Hernandez M, Matha L, Steer CA, Ghaedi M & Takei F . Identification of group 2 innate lymphoid cells in mouse lung, liver, small intestine, bone marrow and mediastinal and mesenteric lymph nodes.  Curr Protoc Immunol  125: e73, 2019. View Abstract


Martinez-Gonzalez I, Ghaedi M, Steer CA, Matha L, Vivier E & Takei F. ILC2 memory: recollection of previous activation.  Immunol Rev  283: 41-53, 2018. View Abstract

Saranchova I, Han J, Zaman R, Arora H, Huang H, Fenninger F, Choi KB, Munro L, Pfeifer CG, Welch I, Takei F & Jeffries WA. Type 2 innate lymphocytes actuate immunity against tumours and limit cancer metastasis.  Sci Rep 8: 2924, 2018.  View Abstract

Sugita K, Steer CA, Martinez-Gonzalez I, Altunbulakli C, Morita H, Castro-Giner F, Kubo T, Wawrzyniak P, Ruckert B, Sudo K, Nakae S, Matsumoto K, O'Mahony L, Akdis M, Takei F & Akdis CA. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions via IL-13 in asthma.  J Allergy Clin Immunol 141: 300-310, 2018. View Abstract



Martinez-Gonzalez I, Matha L, Steer CA & Takei F. Immunological memory of group 2 innate lymphoid cells.  Trends Immunol 38: 423-431, 2017. View Abstract

Steer CA, Martinez-Gonzalez I, Ghaedi M, Allinger P, Matha L & Takei F. Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization.  J Allergy Clin Immunol  140: 593-595, 2017.  View Abstract


Antignano F, Braam  M, Hughes MR, Chenery AL, Burrows K, Gold MJ, Oudhoff MJ, Rattray D, Halim TY, Cait A, Takei F, Rossi FM, McNagny KM & Zaph C. G9a regulates group 2 innate lymphoid cell development by repressing the group 3 innate lymphoid cell program. J Exp Med 213: 1153-1162, 2016. View Abstract

Ghaedi M, Steer CA, Martinez-Gonzalez I, Halim TYF, Abraham N & Takei F. Common- lymphoid-progenitor-independent pathways of innate and T lymphocyte development.  Cell Reports  15: 471-480, 2016.  View Abstract

Martinez-Gonzalez I, Matha L, Steer CA, Ghaedi M, Poon GF & Takei F. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance antigen non-specific allergic lung inflammation.  Immunity  45: 198-208, 2016. View Abstract

Samudio I, Rezvani K, Shaim H, Hofs E, Ngom M, Bu L, Liu G, Lee JT, Imren S, Lam V, Poon GF, Ghaedi M, Takei F, Humphries K, Jia W & Krystal G. UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells.  Blood  127: 2575-2586, 2016. View Abstract


Martinez-Gonzalez I, Steer CA & Takei F. Lung ILC2s link innate and adaptive responses in allergic inflammation.  Trends Immunol 36: 189-195,  2015.  View Abstract


Halim TYF & Takei F. Isolation and characterization of mouse innate lymphoid cells. In:  In Vivo Assays for Mouse Lymphocyte Function., Vol. 106, John Wiley & Sons, Inc., Curr Protoc Immunol  p 3.25.1-3.25.13, 2014.  View Abstract

Halim TYF, Steer CA, Matha L, Gold MJ, Antignano F, McNagny KM & Takei F. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell mediated allergic lung inflammation.  Immunity 40: 425-435, 2014.  View Abstract


Halim TYF, MacLaren A, Romanish MT, Gold MJ, McNagny KM & Takei F. Retinoic acid receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation.  Immunity  37: 463-474, 2012. View Abstract

Halim TYF, Kraub RH, Sun AC & Takei F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36: 451-463, 2012.  View Abstract

Warner K, Luther C & Takei F. Lymphoid progenitors in normal mouse lymph nodes develop into NK cells and T cells in vitro and in vivo. Exp Hematol  40: 401-406, 2012. View Abstract


Luther C, Warner K & Takei F. Unique progenitors in mouse lymph node develop into CD127+ NK cells: thymus-dependent and thymus-independent pathways.  Blood 117: 4012-4021, 2011. View Abstract


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


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


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.


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


Veinotte LL, Greenwood CP, Mohammadi N, ParachoniakCA, & 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


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


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


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


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


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


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


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


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


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


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, JefferiesWA, & 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


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


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


Laura Mathä

Graduate Student

Mona Orangi

Graduate Student

Verena Rinnofner

Dr. Monica Romera-Hernandez

Post Doctoral Fellow

Phoenix Yi Han Yin