Allelic diversity of KIR3DL1/3DS1 in a southern Chinese population

Deng, Zhihui; Zhen, Junjie; Zhu, Bofeng; Zhang, Guobing; Yu, Qi; Wang, Da-Ming; Xu, Yunping; He, Liumei; Lü, Liang

doi:10.1016/j.humimm.2015.09.017

Cited by 7 publications

(3 citation statements)

References 33 publications

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“…Similarly, the majority of East Asian KIR A haplotypes (>70%) express either KIR3DL1 * 001 or KIR3DL1 * 015, which are strongly-inhibitory KIR3DL1 allotypes specific for Bw4 + HLA (44). Of note, the non-expressed KIR3DL1 * 004 allele that is common in Europeans (25) is absent from East Asians (44–46). Thus, in addition to the high frequency of KIR A haplotypes, a given Chinese Southern Han KIR A haplotype is more than twice as likely to express KIR3DL1 * 001 or * 015 than a European KIR A haplotype (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Natural Killer Cells Offer Differential Protection From Leukemia in Chinese Southern Han

et al. 2019

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Interactions of human natural killer (NK) cell inhibitory receptors with polymorphic HLA-A, -B and -C molecules educate NK cells for immune surveillance against tumor cells. The KIR A haplotype encodes a distinctive set of HLA-specific NK cell inhibiting receptors having strong influence on immunity. We observed higher frequency of KIR A homozygosity among 745 healthy Chinese Southern Han than 836 adult patients representing three types of leukemia: ALL (OR = 0.68, 95% CI = 0.52–0.89, p = 0.004), AML (OR = 0.76, 95% CI = 0.59–0.98, p = 0.034), and CML (OR = 0.72 95% CI = 0.51–1.0, ns). We observed the same trend for NHL (OR = 0.47 95% CI = 0.26–0.88 p = 0.017). For ALL, the protective effect of the KIR AA genotype was greater in the presence of KIR ligands C1 (Pc = 0.01) and Bw4 (Pc = 0.001), which are tightly linked in East Asians. By contrast, the C2 ligand strengthened protection from CML (Pc = 0.004). NK cells isolated from KIR AA individuals were significantly more cytotoxic toward leukemic cells than those from other KIR genotypes ( p < 0.0001). These data suggest KIR allotypes encoded by East Asian KIR A haplotypes are strongly inhibitory, arming NK cells to respond to leukemogenic cells having altered HLA expression. Thus, the study of populations with distinct KIR and HLA distributions enlightens understanding of immune mechanisms that significantly impact leukemia pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Natural Killer Cells Offer Differential Protection From Leukemia in Chinese Southern Han

et al. 2019

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“…Frequencies of KIR and HLA class I alleles were obtained from the following populations: Yucpa Amerindians (66), Maori (72), sub-Saharan Africans: Ga-Adangbe from Ghana (73), and Nama and Khomani San from southern Africa (25), Europeans and Papua New Guineans (61), and Chinese Southern Han [(97–99); Deng et al, unpublished]. Heterozygosity was calculated according to Nei and Tajima (100) using the allele frequencies within each population.…”

Section: Methodsmentioning

confidence: 99%

Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates

et al. 2019

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Natural killer (NK) cell functions are modulated by polymorphic killer cell immunoglobulin-like receptors (KIR). Among 13 human KIR genes, which vary by presence and copy number, KIR3DL3 is ubiquitously present in every individual across diverse populations. No ligand or function is known for KIR3DL3, but limited knowledge of expression suggests involvement in reproduction, likely during placentation. With 157 human alleles, KIR3DL3 is also highly polymorphic and we show heterozygosity exceeds that of HLA-B in many populations. The external domains of catarrhine primate KIR3DL3 evolved as a conserved lineage distinct from other KIR. Accordingly, and in contrast to other KIR, we show the focus of natural selection does not correspond exclusively to known ligand binding sites. Instead, a strong signal for diversifying selection occurs in the D1 Ig domain at a site involved in receptor aggregation, which we show is polymorphic in humans worldwide, suggesting differential ability for receptor aggregation. Meanwhile in the cytoplasmic tail, the first of two inhibitory tyrosine motifs (ITIM) is conserved, whereas independent genomic events have mutated the second ITIM of KIR3DL3 alleles in all great apes. Together, these findings suggest that KIR3DL3 binds a conserved ligand, and a function requiring both receptor aggregation and inhibitory signal attenuation. In this model KIR3DL3 resembles other NK cell inhibitory receptors having only one ITIM, which interact with bivalent downstream signaling proteins through dimerization. Due to the extensive conservation across species, selection, and other unusual properties, we consider elucidating the ligand and function of KIR3DL3 to be a pressing question.

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“…It is noteworthy that the high expression allotypes of KIR3DL1 and HLA-B allotypes with 80Ile polymorphisms are both present at higher frequencies in East Asian as compared to Caucasian populations [7,13,[40][41][42], corresponding to the global distribution of CMV-AU.…”

Section: Discussionmentioning

confidence: 99%

Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals

Yawata

Shirane

Woon

et al. 2021

IJMS

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Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions.

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Allelic diversity of KIR3DL1/3DS1 in a southern Chinese population

Cited by 7 publications

References 33 publications

Natural Killer Cells Offer Differential Protection From Leukemia in Chinese Southern Han

Natural Killer Cells Offer Differential Protection From Leukemia in Chinese Southern Han

Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates

Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals

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