KIR/HLA genotype combinations are determinants of Natural Killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC) potency
Bibliographic record
Abstract
Several allelic variants of the killer immunoglobulin-like receptor 3DL1 (KIR3DL1) in combination with their HLA-Bw4 ligands, are associated with protection from HIV infection and/or time to AIDS. The HLA-B*57+KIR3DL1*h/*y genotype combination (KIR3DL1*h/*y encodes high expression receptors) has the most potent effect on slowing time to AIDS in HIV infected individuals. Although this HLA/KIR combination confers natural killer (NK) cells with high functional potential, the mechanism of the AIDS protective effect remains unknown. Indeed, NK cells expressing 3DL1 fail to degranulate upon exposure to autologous HIV-infected CD4+ T-lymphocytes. As HLA-Bw4/KIR3DL1 combinations also endow NK cells with antibody-dependent cellular cytotoxicity (ADCC) functional potential, we hypothesized that NK cells from individuals carrying HLA-B*57+3DL1*h/*y mediate more potent ADCC than NK cells from individuals with less protective HLA/KIR combinations. We compared the ability of NK cells from 39 HIV-uninfected individuals carrying HLA-B*57+3DL1*h/*y (n=11), other HLA-Bw4+3DL1 combinations (n=18), or 3DL1 in the absence of HLA-Bw4 (n=10) to mediate anti-HIV ADCC. Anti-HIV ADCC was measured as the ability of NK cells to deliver granzyme B to HIV gp120-coated CEM.NKr.CCR5 cells (i.e. percent of granzyme B positive cells) in the presence of a common source of anti-HIV antibodies. This GranToxiLux assay efficiently measures ADCC, as target cells do not receive granzyme B in the presence of antibodies from seronegative individuals or F(ab')2 fragments of anti-HIV antibodies. NK cells from HLA-B*57+3DL1*h/*y carriers mediate more potent ADCC (13.4+/-2.61%) than those from individuals carrying other HLA-Bw4+3DL1 combinations (5.15+/-1.54%) or 3DL1 in the absence of HLA-Bw4 (2.78+/-1.48%) (p=0.002, Kruskal-Wallis test, p<0.05 and p<0.01 respectively, Dunn’s Multiple Comparisons test). Therefore, HLA/KIR dependent NK cell “education” is a determinant of ADCC functional potential, and should be taken into consideration when evaluating ADCC as a correlate of disease progression or vaccine efficacy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".