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 discovery that the fetal thymus is a rich source of NK cell progenitors, making it possible to study the differentiation and development of NK cells from fetal progenitors in vitro, and which also provided the first, and still only, method for generating long-lived clones of NK cells from normal mice.  Brooks et al. J. Immunol. 1993; Manoussaka et al. J. Immunol. 160, 2197, 1998;  Fraser et al. Eur. J. Immunol. 2002   
  
• The discovery of the early and potentially critical expression of Ly49E during NK cell development. Toomey et al. Eur.J.Immunol. 28, 47, 1998; Fraser et al. Eur. J. Immunol. 2002   
• The discovery that CD94/NKG2 receptors are responsible for the ability of fetal NK cells to recognize MHC class I deficient cells.  Toomey et al. J. Immunol. 163, 3176, 1999
  
• The discovery that the widely used EL4 and RMA tumour cell lines display mosaic expression of various surface molecules and that RMA and several other commonly used tumour cell lines are in fact all sublines of EL4.  Gays et al. J. Immunol. 2000 
  
• The definition of the cellular and molecular requirements for Qa1-mediated protection of target cells from lysis by NK cells bearing CD94/NKG2A receptors.  Gays et al. J. Immunol. 2001 
  
• The demonstration that soluble IL2 and IL15 are unlikely to act alone to promote the growth and differentiation of NK cells in vivo, and most likely do so only in association with addition factors, in particular IL21.  Toomey et al. J. Leuk. Biol. 2003
  
• The discovery that, uniquely amongst Ly49 receptors, Ly49E can be induced by IL2 or IL15 on mature NK cells, and that the expression of several other NK cell receptors on mature NK cells can be regulated by cytokines. Gays et al. J. Immunol. 2005
  
• The discovery that Ly49B is not normally expressed on NK cells but instead is expressed on various subpopulations of myeloid cells where it forms a constitutive association with the inositol phosphatase SHIP-1, suggesting that it may play an important role in preventing spontaneous activation of myeloid cells in vivo. Gays et al. J. Immunol. 2006
  
• The demonstration that NKRP1D expression is limited to a subpopulation of NK cells, but in contrast to Ly49 receptors is expressed in a normal codominant manner. Aust et al. J. Immunol. 2009
• The discovery that NKRP1D+ NK cells are functionally distinct from NKRP1D- NK cells, NKRP1D+ cells showing reduced expression of various Ly49 receptors, elevated expression of CD94/NKG2 receptors, and higher IFN-γ secretion and cytotoxicity than NKRP1D- cells. Aust et al. J. Immunol. 2009
  
• The demonstration through the creation of Ly49E-knockout mice, that, despite its early expression on immature NK cells, Ly49E is not required for the development or homeostasis of NK and T cell populations or for the acquisition of functional competence in NK cells.  Aust et al. J. Immunol. 2011
  
• The demonstration that functionally distinct members of the Ly49 family show distinct patterns of transcriptional initiation.  Gays et al. Plos One 2011