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HLA alleles determine differences in human natural killer cell responsiveness and potency.


ABSTRACT: Epidemiological studies have associated certain human disease outcomes with particular killer cell Ig-like receptor (KIR) and HLA genotypes. However, the functional explanation for these associations is poorly understood, because the KIRs were initially described as natural killer (NK) cell inhibitory receptors with specificity for HLA molecules on their cellular targets. Yet resolution of infections is often associated with genotypic pairing of inhibitory KIRs with their cognate HLA ligands. Recent studies in mice indicate a second role for MHC-specific inhibitory receptors, i.e., self-MHC recognition confers functional competence on the NK cell to be triggered through their activation receptors, a process termed licensing. As a result, licensed NK cells with self-MHC-specific receptors are more readily activated as compared with unlicensed NK cells without self-MHC-specific receptors. Such results predict that human NK cells may undergo a similar process. Here, we examined the human NK cell subset expressing KIR3DL1, the only known KIR specific for HLA-Bw4 alleles. The KIR3DL1(+) subset in normal donors with two HLA-B-Bw4 genes displayed increased responsiveness to tumor stimulation compared with the KIR3DL1(+) subset from individuals with only one or no Bw4 genes. By contrast, NK cells lacking KIR3DL1 showed no differences. Therefore, these data indicate that particular KIR and HLA alleles are associated with more responsive NK cells, strongly suggesting that human NK cells are also subjected to NK cell licensing, and providing a potential functional explanation for the influence of KIR and HLA genes in disease as well as interindividual differences in NK cell potency.

SUBMITTER: Kim S 

PROVIDER: S-EPMC2268583 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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HLA alleles determine differences in human natural killer cell responsiveness and potency.

Kim Sungjin S   Sunwoo John B JB   Yang Liping L   Choi Taewoong T   Song Yun-Jeong YJ   French Anthony R AR   Vlahiotis Anna A   Piccirillo Jay F JF   Cella Marina M   Colonna Marco M   Mohanakumar Thalachallour T   Hsu Katharine C KC   Dupont Bo B   Yokoyama Wayne M WM  

Proceedings of the National Academy of Sciences of the United States of America 20080219 8


Epidemiological studies have associated certain human disease outcomes with particular killer cell Ig-like receptor (KIR) and HLA genotypes. However, the functional explanation for these associations is poorly understood, because the KIRs were initially described as natural killer (NK) cell inhibitory receptors with specificity for HLA molecules on their cellular targets. Yet resolution of infections is often associated with genotypic pairing of inhibitory KIRs with their cognate HLA ligands. Re  ...[more]

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