In the past year significant progress has been made in the investigation of the function and transcriptional control of human and mouse class I major histocompatibility complex (MHC) receptors expressed on natural killer (NK) cells. We have identified and characterized probabilistic transcriptional switches in the human killer cell immunoglobulin-like receptor (KIR) genes, similar to the switches that we described in the murine Ly49 gene family. A series of genetic polymorphisms have been characterized in the human switch elements, and the functional relevance of these polymorphisms has been demonstrated. We are collaborating with Dr. Jeffrey Miller at the University of Minnesota Cancer Center, an expert on human NK cell differentiation and bone marrow transplantation to exploit our novel findings. This discovery has important implications for the control of stem cell differentiation, and may one day allow us to modify cell fate in differentiating systems such as bone marrow cultures. Our work has defined a novel paradigm for the selective activation of genes, and we are the pioneers in this area. My group is also investigating a novel spliced KIR antisense transcript that is controlled by a promoter that appears to be active only in precursor or stem cell populations. This discovery suggests that specific silencing RNA is generated to prevent expression of the KIR genes in precursor cells or non-NK lineages. In addition, we have continued to work on the structure and function of the Ly49 gene family in collaboration with Dr. Andrew Makrigiannis, a former postdoctoral fellow who has established an independent laboratory at McGill University (Montreal, Canada). We have recently succeeded in deleting all of the class I MHC receptor genes from the 129 mouse strain. These mice will be extremely valuable for gaining a complete understanding of the role of these receptors in NK cell development and function. I am also collaborating with Dr. Makrigiannis on the generation of a complete set of peer-reviewed Ly49 molecule pages for the AfCS-Nature signaling gateway, and five of these have been accepted and published online this year.
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