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THE MINIMAL ESSENTIAL KIR RECEPTOR IN HUMANS.
Zeying Du Ph.D. , John Muramoto , Elaine F. Reed Ph.D. and Raja Rajalingam Ph.D. . 1 UCLA Immunogenetics Center, Dept. of Pathology and Lab. Medicine, Los Angeles, CA .
Interactions between KIR and HLA class I molecules regulate NK cell function. KIR and HLA are encoded by unlinked polymorphic gene families, and their independent segregation results inheritance of variable number and type of KIR-HLA pairs in individuals. The aim of the present study is to identify the simplest KIR-HLA combination in humans that could enable NK cells to perform the minimal essential function. We characterized KIR genes in 625 unrelated individuals representing most ethnic groups. One third of the panel (n=188, 30%) carried the simplest genotype: 3DL3-2DL3-2DP1-2DL1-3DP1-2DL4-3DL1-2DS4-3DL2. Three of these genes are either psudogenes (2DP1 and 3DP1) or untranscribed (3DL3). KIR2DL4 unlikely mediates peripheral tolerance since it recognizes trophoblast-specific HLA-G. Subtyping of 2DS4 on these 188 individuals revealed that 41% of them (n=77) carry only 2DS4*003 allele, which is not expressed due to a deletion in exon-5. Therefore, 12% of our study panel does not have any activating KIR gene, and posses only 4 inhibitory KIRs: 2DL3, 2DL1, 3DL1, and 3DL2. The inhibitory function of these receptors however depends on the presence of their cognate HLA ligand. HLA typing on these individuals revealed that only 2 Asians carry ligands for all 4 inhibitory KIRs, but majority (n=25) had only one ligand, which is HLA-C. Interestingly, 22 of them carry only HLA-CN80 motif, which is recognized by the weakly interacting 2DL3 receptor. Therefore, 4% of the human population has only a weak inhibitory 2DL3-CN80 combination, which could provide the essential inhibitory signal to NK cells to mediate tolerance to self. Environmental challenges particularly that affect the HLA-C expression in these individuals may breakdown the self-tolerance and trigger autoimmunity.