Deciphering impact of immunoreceptor tyrosine-based activation motifs in natural killer cells

About This Grant

PROJECT SUMMARY Natural killer (NK) cells are critical members of the immune system tasked with recognizing and eliminating harmful cells, including virally infected and cancerous cells. They recognize harmful cells (target cells) through membrane bound NK receptors (NKR) that interact with ligands on the surface of targets. Upon cross-linking of activating NKRs, immunoreceptor tyrosine-based activating motifs (ITAM) on adaptor molecules get phosphorylated and initiate signaling cascades that result in the activation of NK cells – and ultimately kill targets. Since their discovery, ITAMs have always been regarded as only driving activating signals. However, recent studies suggest that there are nuances to this activation and there may be scenarios where ITAMs suppress immune cell activation. Given that NK cells play a critical role in protection from harmful cells and that many of their activating NKRs depend on ITAM-containing adaptor molecules, understanding the signaling cascades that achieve optimal NK cell activation is fundamental to enhance cellular therapies. This is particularly important as numerous reports demonstrate that immune cells face a strong immunosuppressive environment in some diseases, including in the tumor microenvironment. In this proposal, we will investigate the roles that ITAMs play in activating NK cells. We will achieve this by using mouse models whereby their NK cells express mutant adaptor molecules whose ITAMs are incapable of activation. Using these mutant ITAM-deficient mice, i) we will determine if ITAMs influence NK cell development, ii) if ITAMs influence phenotypic differences in NK cells, and iii) if ITAMs calibrate the responsiveness of NK cell to harmful cells. We will also begin to elucidate if signaling through ITAM- bearing receptors impacts cellular fates of NK cells. NK cells have been documented to exhibit adaptive-like features with enhanced secondary responses and increased longevity, therefore understanding the factors that promote adaptive NK cell formation are critical. To achieve these answers, we will use in vitro and in vivo models of cancer and viral infection to assess NK cell function and use cutting-edge technologies to assess NK cell phenotypes. In summary, these studies will investigate the importance that ITAMs contribute to overall NK cell fitness and driving NK cells with enhanced protective features. These studies have the potential to greatly enhance NK cell based cellular therapies in the clinic.