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Research

Electron micrograph of an NK cell

        The main interest of the lab currently focusses on the development, recognition capabilities, and function of NK [natural killer] cells.  NK cells are a major population of lymphocytes found in humans and all vertebrate animals.  They play a critical role in defence against infectious disease, having the ability to recognize and kill cells infected with a variety of viruses, and also being major contributors to the early production of cytokines following infection with  viruses and other parasites.  It is also clear that NK cells participate in the rejection of transplanted tissues, especially transplanted bone marrow and lymphoid cells, and in certain autoimmune diseases.  Their ability to spontaneously kill tumour cells in vitro  suggests that they may protect animals against malignant disease and that it may be possible to harness NK cells therapeutically for the treatment of cancer, a proposition supported by numerous studies showing that NK cell depletion causes reduced resistance to tumour growth.   

        A major advance in our understanding of  NK cells was the discovery that they employ a novel form of recognition, known as “missing self” recognition, that allows them to detect diseased or infected cells that have reduced expression of MHC class I molecules.  At the molecular level this is achieved via the expression on NK cells of at least three families of receptors for class I molecules, the CD94/NKG2 family [which is present on NK cells from all species] and either the Ly49 family [which is expressed in rodents and certain other species] or the KIR family [which is expressed in humans and other primates].  Despite appearing to have identical functions, the Ly49 and KIR receptors have radically different structures, the former belonging to the C-type lectin superfamily and the latter to the Ig superfamily, providing one of the most remarkable examples of convergent evolution yet uncovered.  MHC class I receptors are not expressed in the normal codominant manner, but in an unsusual and poorly understood stochastic manner, such that each individual NK cell expresses at random a limited number of all of the class I receptors in its genome, creating a large and complex repertoire of NK cells in which to a first approximation each NK cell has a different permutation of class I receptors.  NK cells also express many other receptors, such as those belonging to the NKRP1, CLR, and NCR families.  Despite intensive investigation, the processes involved in the creation of this diverse NK cell repertoire are still poorly understood.  Most available evidence supports a model in which the stochastic expression of Ly49, KIR, and CD94 receptors is triggered at a critical stage in development.  This creates a naive repertoire that is subjected to “positive and negative” selection, resulting in the loss or anergization of those cells that fail to express any receptors for self class I molecules, and allowing the maturation of those cells that express at least one receptor for self class I molecules, a phenomenon, sometimes referred to as "education" or "licencing".

        The research performed in our laboratory in the University of Newcastle has led to significant advances in our understanding of NK cells and the receptors they bear.  Some of our main findings have been:
Our work has been funded by a series of grants from the Medical Research Council, the Biotechnology and Biological Sciences Research Council, the Cancer Research Campaign, and the University of Newcastle.   We have collaborated with many scientists in Newcastle, elsewhere in the U.K., and in other countries. 


High power view of an NK cell granule containing perforin, granzymes, and other mediators

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