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. 2014 Oct;44(10):2938-48.
doi: 10.1002/eji.201444751. Epub 2014 Aug 12.

Increased frequency and function of KIR2DL1-3⁺ NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes

Christian Körner  1 , Mitchell E Granoff, Molly A Amero, Michael N Sirignano, Sagar A Vaidya, Stephanie Jost, Todd M Allen, Eric S Rosenberg, Marcus Altfeld
Affiliations

Increased frequency and function of KIR2DL1-3⁺ NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes

Christian Körner et al. Eur J Immunol. 2014 Oct.

Abstract

The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1-positive and HIV-1-negative individuals were assessed (N = 42 and N = 40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3(+) NK cells. Further analysis showed that KIR2DL1(+) NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3(+) NK cells. KIR2DL1-3(+) NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes, as measured by degranulation and IFN-γ and TNF-α production. These results identify a novel relationship between HLA-C and KIR2DL(+) NK-cell subsets and demonstrate that HLA-C-mediated licensing modulates NK-cell responses to primary HIV-1 infection.

Keywords: HIV-1; HLA-C; Inhibitory killer-cell immunoglobulin-like receptors (KIRs); Natural killer (NK) cells.

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Figures

Figure 1
Figure 1. Frequency of KIR2DL1-3+ NK cells in primary HIV-1 infection stratified by HLA-C group haplotypes
(A) Frequency of NK cells expressing at least one KIR2DL1-3 receptor in HIV-1(-) and HIV-1(+) individuals. (B) Percentage of KIR2DL1+ and (C) KIR2DL2/3+ NK cells in HIV-1(-) and HIV-1(+) individuals stratified by their HLA-C group haplotype. HIV-1(-): n=40; HIV-1(+): n=42. Haplotypes of HLA-C are indicated as follows: 1/1=C1/C1, 1/2=C1/C2, 2/2=C2/C2. Scatter plots display frequency of KIR-expressing NK cells for each individual as well as median for each group. Mann-Whitney test (A) and Kruskal-Wallis test following Dunn's post-test (B) were used to test for differences between groups.
Figure 2
Figure 2. KIR2DL1-3+ and NKG2C+ NK cell frequencies in HIV-1(+) and HIV-1(-) individuals stratified by CMV serostatus
Frequency of (A) KIR2DL1-3+ and (B) NKG2C+ NK cells in HIV-1(-) and HIV-1(+) CMV-seronegative/positive individuals. Proportion of (C) KIR2DL1+ and (D) KIR2DL2/3+ NK cells in HIV-1(-) and HIV-1(+) individuals stratified by their HLA-C group haplotype and CMV serostatus. HIV-1(-): n=40; HIV-1(+): n=42. Haplotypes of HLA-C are indicated as follows: 1/1=C1/C1, 1/2=C1/C2, 2/2=C2/C2. Scatter plots display frequency of receptor-expressing NK cells for each individual as well as median for each group. Kruskal-Wallis test following Dunn's post-test was used to test for differences between groups.
Figure 3
Figure 3. Comparison of NK cell responses between KIR2DL1-3+ and KIR2DL1-3(−) NK cell subsets in primary HIV-1 infection
Functional assessment of KIR2DL1-3-expressing NK cell subsets in HIV-1(+) individuals carrying at least one copy of the cognate HLA-C group allele (KIR2DL1+/HLA-C2+; KIR2DL2/3+/HLA-C1+): (A) Paired comparison between KIR2DL1 single-positive NK cells and KIR-negative NK cells (n=24); (B) paired comparison between KIR2DL2/3 single-positive NK cells and KIR-negative NK cells (n=32). Single-positive KIR NK cells are defined as expressing either KIR2DL1, or KIR2DL2/3 but not KIR3DL1. KIR-negative NK cells are defined by the absence of KIR2DL1, KIR2DL2/3 and KIR3DL1 on the cell surface. Scatter plots display frequency of CD107a+, IFN-γ and TNF-α producing NK cells as well as percentage of polyfunctional NK cells (CD107a+/IFN-γ+/TNF-α+) for each individual. Wilcoxon matched-pairs signed rank test for paired values was used to test for differences between groups.
Figure 4
Figure 4. Frequency of functional NK cells expressing KIR2DL1-3+ stratified by type of response and HLA-C group haplotypes
Pie charts display median percentage of functional NK cells expressing KIR2DL1 or KIR2DL2/3 stratified by HLA-C group haplotypes of the respective HIV-1(+) individuals. Functional NK cell subsets are defined either as CD107a+ NK cells, IFN-γ or TNF-α+ producing NK cells or polyfunctional NK cells (CD107a+/IFN-γ+/TNF-α+). Haplotypes of HLA-C are indicated as follows: 1/1=C1/C1, 1/2=C1/C2, 2/2=C2/C2. Kruskal-Wallis test following Dunn's post-test was used to test for differences between groups.
Figure 5
Figure 5. Paired comparison of NK cell phenotype and function between primary and early chronic HIV-1 infection
Changes in frequency of KIR2DL1-3+ NK cells (A), percentages of IFN-γ, TNF-α producing and polyfunctional (CD107a+/IFN-γ+/TNF-α+) NK cells (B). Scatter plots display frequency of above mentioned NK cell subpopulations for each individual (n=36). (C) Correlation plots displaying the differential between NK cell responses in primary and in early chronic infection for bulk as well as self-inhibitory KIR+ and KIR(−) NK cell subsets. * Self-inhibitory KIR+ NK cells are defined as follows: NK cells expressing KIR2DL1-3 and/or KIR3DL1 in individuals carrying the cognate HLA-C group allele or HLA-Bw4 allele. * Self-inhibitory KIR(−) NK cells are characterized by the lack of the mentioned self-inhibitory KIR in the respective individuals. Wilcoxon matched-pairs signed rank test for paired values was used to test for differences between groups. Differential was calculated as follows: Δ % response = [% response (early chronic infection) - % response (primary infection)]. Linear regression analysis was used to test for differences between the slopes of the NK cell subsets.
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