Natural killer cells are so named because of their ability to spontaneously lyse transformed or virally infected cells. Individuals lacking NK cells or NK cell function suffer from life-threatening opportunistic viral infections including human cytomegalovirus and herpes simplex virus infections. In addition to the destruction of defective cells NK cells also secrete cytokines such as IFN-gamma, TNF-alpha, and GM-CSF to further drive the immune response and help to initiate adaptive immunity.
Control of NK cell function is absolutely vital to protect the host from autoimmunity. NK cells express a plethora of receptors that negatively and positively regulate their function. Prominent among these are the C-type lectin-like Ly49 family of class I MHC receptors. The recognition of normal MHC expression by inhibitory Ly49 on healthy cells spares them from NK cell attack. However, MHC can be downregulated after virus infection or transformation, resulting in NK cell lysis (Fig. 1).
The multigene Ly49 family is found on mouse chromosome 6 and is extremely polymorphic in terms of allelic variability and gene numbers among different Ly49 haplotypes (Fig. 2). Mapping and sequencing of bacterial artificial chromosome genome libraries of common inbred mouse strains has shown that the commonly used C57BL/6 inbred mouse has a unique haplotype shared only with C57BL/10. We have found that most common inbred mouse strains possess Ly49 haplotype represented by the BALB/c and 129 inbred mouse strains. We first sequenced 129 haplotype (650 kb; 20 genes) and is larger than the C57BL/6 cluster. On the other hand, the BALB/c Ly49 cluster is very small at 300 kb with about 8 genes. The absence of the Ly49h gene in the BALB/c cluster correlates with the lack of MCMV resistance in this mouse strain. Mouse Ly49 haplotype variability in gene number is a shared characteristic with the human functional analogues, the KIR.
Most recently, we are extending our Ly49 haplotype analysis to the non-obese diabetic (NOD) mouse strain. Initial observations include a greatly expanded repertoire of activating Ly49, a characteristic that is shared with human diabetics. Future research will involve assessing global Ly49 cluster impact on NK cell function via gene deletion approaches.
Figure 1 :
Last updated: April 02, 2015