Laboratory Description
Research in my laboratory focus on fundamental aspects of human lymphocyte effector functions, and we are currently specifically interested in understanding the immunobiology of Natural Killer (NK) cells. NK cells are bone-marrow-derived lymphocytes capable of mediating early innate immune responses to virally infected cells and transformed malignant cells. Critical to innate immunity, the NK cell performs its function of immunosurveillance through its recognition of altered or missing self on damaged, infected or transformed malignant cells.
NK receptors responsible for detection of HLA class I and class I-like proteins on potential target cells transmit inhibitory and activating signals that integrate to determine NK function. Advances in the fields of NK receptor biology and immunogenetics have enhanced our understanding of NK target recognition and may now guide studies to determine NK effect in the clinical setting. Analysis of NK receptor-ligand relationships such as the inhibitory killer immunoglobulin-like receptors (KIRs) and their HLA class I ligands has revealed the potential for NK cell-mediated benefit in allogeneic hematopoietic stem cell transplantation for hematologic malignancies.
Together with dendritic cells (DCs), NK cells provide an essential function in immunity by initiating immune responses and by coordinating an orderly transition from innate to adaptive immunity. In a simplified model for an immune response to a pathogen, immature DCs (iDC) located in peripheral tissues take up pathogens and become mature DCs (mDCs), which are then transported to secondary lymphoid tissues where the immune response is initiated. In the periphery, iDC can activate NK cells by their production of the cytokines IL-2, IL-12, IL-15 and IL-18, and DC production of TNF-a will induce NK cytotoxicity.
In inflammatory tissues, CD56dim cytotoxic NK cells may remove iDC due to their low expression of MHC class I, while sparing mDC that have upregulated MHC class I and express both HLA-E and classical MHC class I molecules. Lysis of iDC in the periphery may then facilitate local antigen release, antigen uptake and possibly cross-presentation of antigen. In the lymphoid tissues, CD56bright NK cells become activated by IL-2 and IL-12 produced by mDCs. The resulting NK cell production of IFN-gamma and granulocyte-macrophage-colony stimulating factor (GM-CSF) induces T helper cell differentiation and Th1 polarization and promotes DC survival and differentiation. Additional cytokines released from the DC can induce NK cell differentiation and maturation and can facilitate NK cell exit as mature effector cells.
The prevailing concept explaining regulation of NK cell activity takes into account both the "missing self recognition hypothesis" and the recent findings that NK cells become activated through ligand binding to the activating receptor NKG2D, even when the target cell expresses normal amounts of HLA class I molecules. While the natural ligands for NKG2D are encoded by genes within the human genome, expression of sufficient ligands on target cells for activation of NKG2D requires induction of gene expression. NKG2D-mediated NK cell activation in presence of "self" HLA is therefore referred to as the "induced self recognition hypothesis".
Other activating NK receptors, called natural cytotoxicity receptors (NCRs) are also capable of overriding the inhibition mediated by inhibitory NK receptors with ligand specificity for HLA class I molecules. Our studies utilize a combination of techniques such as imaging of NK cell:target cell interactions, biochemical characterization of signal transduction pathways, target cell and NK cell modification via gene transfer and application of immunogenetic principles for designing the experimental models to be tested. Other studies focus on translational research projects comparing genomic analysis of genes encoding the humans major histocompatibility complex (MHC)-HLA- with genetic variation in genes encoding receptors expressed on NK cells.
