Using NK Cell Mediated Cytolysis to Trigger Adaptive Immune Responses

The vertebrate immune system is an enormously complex arrangement of a large number of interdependent cell types, responsible for fending off harmful invasive organisms as well as aberrant cells within the host itself. The system is divided into two broad arms; the innate and the adaptive immune compartments. Whereas the cells of the innate arm recognizes threats based on certain characteristics common to most invaders, adaptive immune cells is able to recognize billions of unique antigens due to specialized receptors on their surface. This ability is dependent on an efficient means of exposing the cells to antigenic peptides, achieved through a mechanism known as antigen presentation. Several cell types, commonly referred to as professional antigen presenting cells (pAPCs), are able to carry out this function; most well known of these are the dendritic cells (DCs). However, difficulties in growing DCs in vitro has led to an increased interest in using alternative APCs to expand robust adaptive immune responses for clinical use. By using CD40 activated B cells as an alternative APC, we observed a significant difference in T cell expansions towards specific antigens. Efficient antigen presentation requires the two distinct immune compartments to act in unison, where cell-mediated lysis carried out by the innate system generate antigenic peptides for activation of adaptive responses. Natural killer (NK) cells are innate immune cells, capable of eliminating virus infected or cancer-transformed cells without prior activation, an ability that coined the term natural killer . NK cells are regulated through signaling from a diverse array of activating and inhibiting receptors, with stress proteins acting as ligands for the activating receptors, and MHC molecules generally acting as ligands for inhibitory receptors. In this thesis we hypothesized that NK mediated cytolysis can bridge innate and adaptive immunity and prime systemic T cell reactivity. NK cells are able to respond quickly to cells that express stress markers, or lose expression of MHC molecules, characteristics that are generally associated with malignancy. It is possible that this innate recognition of transformed cells contributes to a more efficient priming of adaptive immune responses by generating peptide fragments readily available for presentation to T cells. Using a step-wise in vitro model system of T cell priming we found evidence of improved T cell expansions as a result of being stimulated with peptide fragments obtained through NK cell mediated cytolysis of a melanoma cell line. This stimulation also led to an increase in epitope specific cells against a known melanoma antigen, MART-1. Although further investigations are needed, exploiting NK cell cytolysis and natural fragmentation of tumor associated antigens may hold utility in the development of cancer vaccines by providing new insights into tumor specific epitopes and neo-antigens