NK cell is an important component of the innate immune response against virally infected and malignant cells. Originated from hematopoietic stem cells, the development of NK cells requires less interactions with bone marrow stromal cells, which are not completely understood. (Hamerman et al., 2005). In peripheral tissue, two major functions of NK cells have been described. First, NK cells are effector cells which directly kill target cells through a largely perforin-dependent mechanism. Second, NK cells express arrays of cell surface molecules and secrete cytokines, which regulate immune responses in the site of infection or inflammation (Zingoni et al., 2005). As a consequence of target cell cytolysis by NK cells, more bacterial, viral, or tumor antigens may be provided to professional antigen-presenting cells for initiation of adaptive immunity. Finally, through cell-cell interaction or cytokine, NK cells could enhance the functions of antigen-presenting
Lieping Chen • Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Jefferson 1-121, Baltimore, MD 21205
CD137 Pathway: Immunology and Diseases. Edited by Lieping Chen, Springer, New York, 2006
cells and lymphoid cells. Therefore, an important role ofNK cells appears to bridge innate and adaptive immunity.
While resting NK cells express negligible CD137, activation ofNK cells by IL-2orIL-15 leads to surface expression ofhigh level CD137 (Melero etal., 1998). The number ofNK and NKT cells decreases significantly in CD137-deficient mice (Kwon et al., 2002), suggesting that CD137 may affect the development ofNK cells. Stimulation by CD137L-transfected cells or CD137 agonistic monoclonal antibodies (mAb) induced vigorous proliferation ofNK cells and IFN-y secretion in vitro (Wilcox et al., 2002). However, cytolicic activity ofNK cells against NK-sensitive target cells, was not changed in the same stimulation condition. There are several important implications from these findings. First, cytolytic and immune regulatory functions of NK cells could be segregated and controlled by distinct mechanisms. Second, manipulation of CD137 pathway provides a unique opportunity to selectively regulate immune regulatory functions ofNK cells. Thus, these findings may provide explanations for several previous observations which could not be satisfactorily interpreted.
Administration of either CD137 agonist mAb or recombinant CD137L has been shown to induce complete or partial regression of established tumors in various mouse models (Hellstrom and Hellstrom, 2003; also see summary in Chapter 8). In tumor models in which the role ofNK cells were analyzed, antitumor immunity was either completely, or at least partially dependent on NK cells. This is proven by showing decreased tumor immunity CTL activity by depletion of NK cells using either a polyclonal or mAb (Melero et al., 1998, Wilcox et al., 2002b, Ye et al., 2002). However, for a NK-resistant P815 mouse tumor, anti-CD137 mAb does not inhibit tumor growth in immunodeficient BALB/c nu/nu mice, in which NK activity is elevated. However, in immunocompetent syngeneic mice, treatment by anti-CD137 mAb induced the regression, but the depletion ofNK cells completely eliminated the induction of CTL and tumor immunity (Melero et al., 1998). In this system, the effect ofNK cells could be entirely attributed to their immune regulatory function because P815 is resistant to NK cell lysis. In a liver metastasis model of MCA206 mouse colon cancer, adenovirus-mediated gene transfer of both CD137L and IL-12 gene into tumor cells led to the regression of established tumors, accompanied with increased NK activity (Martinet et al., 2000). Depletion ofNK or CD8+ T cells in this system also largely abolished the antitumor immunity. Similarly, NK cells are also partially required for CD8+ CTL induction and tumor immunity in a C3 tumor model (Wilcox et al., 2002b). These results thus support a regulatory function ofNK cells after activation by CD137.
Although the immune regulatory function ofNK cells has been a subject of research for a long period of time, the mechanisms underlying these observations are not yet elucidated. CD137 is a potent inducer of IFN-y from T cells and NK cells and blocking IFN-y eliminated various effects ofanti-CD137 mAb, including induction ofT cell activation and tumor immunity (Wilcox etal., 2002a). Therefore, the effect ofNK cell activation by CD137 signal is at least partially dependent upon secretion of cytokines. Several recent studies support a critical role ofNK cells in activation of dendritic cells that are critical antigen presenting cells (Degli-Esposti and Smyth, 2005). In MCA206 tumor model, antitumor effect and NK
cell activation by CD137L and IL-12 are accompanied by an increased influx of DC infiltrated into tumors and enhanced T cell stimulatory function (Pan et al., 2004). Therefore, enhancing regulatory function of NK cells in vivo may represent a useful approach to enhance adaptive immunity.
The study of the role of CD137 signal in development, activation, and functional modulation of NK cells is essential for understanding mechanisms of CD137 in regulating immune responses. Current data has established a role of CD137 signal in the regulation of NK activity and supports that CD137 signaling may represent a critical link between innate and adaptive immune responses.
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