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

Sung Jin Kim, John B. Sunwoo, Liping Yang, Taewoong Choi, Yun Jeong Song, Anthony R. French, Anna Vlahiotis, Jay F. Piccirillo, Marina Cella, Marco Colonna, Thalachallour Mohanakumar, Katharine C. Hsu, Bo Dupont, Wayne M. Yokoyama

Research output: Contribution to journalArticle

181 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3053-3058
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number8
DOIs
StatePublished - Feb 26 2008
Externally publishedYes

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Natural Killer Cells
Alleles
Licensure
Natural Killer Cell Receptors
Genes
HLA-B Antigens
Mental Competency
Epidemiologic Studies
Genotype
Ligands
Infection

Keywords

  • Innate immunity
  • Killer cell Ig-like receptor (KIR)
  • Licensing
  • NK cells

ASJC Scopus subject areas

  • General

Cite this

HLA alleles determine differences in human natural killer cell responsiveness and potency. / Kim, Sung Jin; Sunwoo, John B.; Yang, Liping; Choi, Taewoong; Song, Yun Jeong; French, Anthony R.; Vlahiotis, Anna; Piccirillo, Jay F.; Cella, Marina; Colonna, Marco; Mohanakumar, Thalachallour; Hsu, Katharine C.; Dupont, Bo; Yokoyama, Wayne M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 8, 26.02.2008, p. 3053-3058.

Research output: Contribution to journalArticle

Kim, SJ, Sunwoo, JB, Yang, L, Choi, T, Song, YJ, French, AR, Vlahiotis, A, Piccirillo, JF, Cella, M, Colonna, M, Mohanakumar, T, Hsu, KC, Dupont, B & Yokoyama, WM 2008, 'HLA alleles determine differences in human natural killer cell responsiveness and potency', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 8, pp. 3053-3058. https://doi.org/10.1073/pnas.0712229105
Kim, Sung Jin ; Sunwoo, John B. ; Yang, Liping ; Choi, Taewoong ; Song, Yun Jeong ; French, Anthony R. ; Vlahiotis, Anna ; Piccirillo, Jay F. ; Cella, Marina ; Colonna, Marco ; Mohanakumar, Thalachallour ; Hsu, Katharine C. ; Dupont, Bo ; Yokoyama, Wayne M. / HLA alleles determine differences in human natural killer cell responsiveness and potency. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 8. pp. 3053-3058.
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T1 - HLA alleles determine differences in human natural killer cell responsiveness and potency

AU - Kim, Sung Jin

AU - Sunwoo, John B.

AU - Yang, Liping

AU - Choi, Taewoong

AU - Song, Yun Jeong

AU - French, Anthony R.

AU - Vlahiotis, Anna

AU - Piccirillo, Jay F.

AU - Cella, Marina

AU - Colonna, Marco

AU - Mohanakumar, Thalachallour

AU - Hsu, Katharine C.

AU - Dupont, Bo

AU - Yokoyama, Wayne M.

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N2 - 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.

AB - 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.

KW - Innate immunity

KW - Killer cell Ig-like receptor (KIR)

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