Basic Properties of Natural Killers

NK cells cytotoxicity is executed by the massive degranulation of perforin and granzymes, eliciting a fast apoptosis of the opponent target cell [3, 4]. Perforin proteins polymerize to form permeable pores in the membrane of targeted cells. Through

Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

E. Yefenof (ed.), Innate and Adaptive Immunity in the Tumor Microenvironment. © Springer 2008

these pores granzymes enter and activates a robust caspase-pathway of apoptosis which results in a rapid cell death [5]. Naïve NK cells contain granules that store perforin and granzymes, prior to stimulation, giving them the Large Granular Lymphocytes (LGL) appearance [3]. This is why NK cells are immediate potent killers. However, in most cases tumors are not efficiently killed by circulating unstimulated NK cells, and the efficient cytotoxicity is evident only upon IL-2, IL-12, IL-15 or IFNa stimulation [6, 5]. NK cells can also use other means of destruction such as the FasL, TNFa and TNF related apoptosis inducing ligand (TRAIL), that induce apoptosis of cancerous cells, albeit with a slower kinetics [3, 7]. These alternative killing pathways play a secondary role as evident from the poor NK cytotoxicity in perforin knockout mice [8], and in human perforin-deficiency cases [9].

Beside their efficient killing ability, NK cells also secret cytokines and chemok-ines, notably IFNg [3, 5]. The secretion of growth factors influences immunity in general, and NK cells were demonstrated, for example, to play an essential role in the polarization of immune response towards the TH1type by providing the major source of IFNg in the lymph node [10]. In addition, NK cells by themselves may act as Antigen Presenting Cells (APCs) [11], and they demonstrate a complex direct interactions with professional APCs such as Dendritic cells (DCs) [12] and macrophages [13]. This APCs network might be useful for example on the transfer of MHC loaded with peptides from one cell type to another (NK, DCs or macrophages), for fine-tuning of the quality and magnitude of T cell response.

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