My laboratory studies the development and functions of natural killer (NK ) cells.Our long term goal is to specifically augment the cytotoxic potentials of human NK cells and to successfully kill and clear tumor in patients.
NK cells are the major effector lymphocytes of innate immune system that defend against many forms of viral infections and tumor growth. NK cells are granular, bone marrow-derived lymphocytes capable of executing ‘natural cytotoxicity’ without prior sensitizations. NK cells bridge innate and adoptive immune responses through the secretion of a variety of cytokines and chemokines. Effector phase of NK cells are regulated by inhibitory and activating receptors. A signaling balance between the inhibitory and activating receptors determine the NK cell functions. NKG2D recognizes ‘induced-self’ ligands on tumor and virally infected cells. NCRs primarily recognize viral hemagglutinin (HA) on infected cells. Therefore, a better understanding of signaling events downstream of these two receptor systems in both murine and human NK cells is essential for successful formulation of NK-based cellular immunotherapies. Our long-term goals are to determine, evaluate and apply the molecular mechanisms that govern NK cell activation and its responses to viral and tumor challenges.
- NKG2D- and NCR1-mediated signaling in NK cells
- NK cell-mediated anti-influenza responses in the lung
- Expression and functions of NK activating ligands during influenza infection (NO1)
Activation through NKG2D and NCRs results in cytotoxic granule release, cytokine/chemokine generation and NK trafficking. NKG2D uses DAP10 and DAP12 to launch two signaling cascades. In the first, activated PTK phosphorylates YINM motif-bearing DAP10, which recruits PI3K-p85α. In the second, PTK phosphorylates the ITAM-containing DAP12 that triggers Syk and ZAP70, leading to the activation of PLC-γ2 pathway. Human NK has three NCRs while the murine NK express only NCR1 (NKp46). NCRs associate with CD3ζ and FcRγ(for NKp30 and NKp46), or DAP12 (for NKp44). Signaling events downstream of NCRs are yet to be determined. How these two activation receptor systems coordinate their activation cascades during viral clearance is of significant clinical relevance. At present, we are using multiple gene knockout mice to generate a detailed map of signaling events in NK cells.
NKG2D and NCRs are ubiquitously expressed on murine and human NK cells. NKG2D recognizes inducible self proteins as ligands while NCR interacts with influenza-derived HA proteins. Currently, nine murine and five human proteins have been defined as ligands for NKG2D receptor. These include ULBP (1-5), MIC (A & B) in human and H60 (a, b & c), Rae-1 (α, β, γ, δ & ε), Mult1 in mice. NKG2D ligands belong to non-classical MHC class I family and are inducible by multiple stress stimuli; therefore, defined as ‘induced-self’. These self-proteins are expressed due to pathological stimuli (such as influenza infection), share limited amino acid homology and form the molecular basis for NKG2D-mediated activation. During the course of identifying minor histocompatibility antigens, we determined the molecular identity of one of these ligands, H60a. This finding has opened newer avenues for our study. Currently, we are studying the molecular mechanisms by which the expression of these ligands is induced.
Rajasekaran Kamalakannan, PhD
Research Scientist I
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