Lessons learned: natural killer cell education as a determinant of the anti-viral functional potential of natural killer cells
Notice bibliographique
Résumé
A vaccine against the human immunodeficiency virus (HIV) is urgently needed. Recent estimates predict that 34 million people are currently infected with HIV. Attempts to induce potentially protective cytotoxic T-lymphocytes or broadly neutralizing antibodies by vaccination have either proven unsuccessful or failed to elicit the desired immune responses. However, the recent RV144 vaccine trial that provided partial protection against HIV infection appears to have induced antibodies that can utilize cells of the innate immune system, such as natural killer (NK) cells, to mediate antibody-dependent cellular cytotoxicity (ADCC) against HIV-infected cells. This potential mechanism of protection corroborates recent epidemiological and functional studies demonstrating that HIV-exposed seronegative individuals (HESN) and HIV-infected slow progressors (SP) have higher functioning NK cells and carry certain allelic combinations of killer immunoglobulin-like receptors (KIR) and their major histocompatibility complex class I (MHC-I or HLA-I) ligands that confer NK cells with enhanced functionality. Cumulatively, these observations suggest that understanding the conferral of functional potential during NK cell ontogeny could be important for designing anti-HIV vaccine constructs. In particular, data from HESN and SP have demonstrated that allelic combinations of KIR3DL1 and its HLA-Bw4 ligand are associated with protective outcomes in the context of HIV. Although previous work has demonstrated thatinteractions between these receptor ligand combinations during NK cell development confers NK cells with functional potential, the exact mechanism of the protective outcomes in the context of HIV remain unknown. For example, KIR3DL1+ NK cells have been demonstrated to be hypofunctional in the presence of autologous HIV-infected T cells. This suggests that if KIR3DL1+ NK cells are providing protection through mediating function, they require additional activating signals. As previously published data has demonstrated that activation through CD16a by antibody constant regions can overcome KIR-mediated NK cell inhibition and lead to ADCC of allogeneic cells, we hypothesized that ADCC could overcome inhibitory signalling and allow KIR3DL1+ NK cells to respond to autologous anti-HIV ADCC target cells. The data presented in this thesis reaffirms that HIV protective KIR3DL1/HLA-Bw4 allelic combinations confer enhanced functional potential upon NK cells. The results presented demonstrate that KIR3DL1/HLA-Bw4 combinations educate NK cells for enhanced anti-HIV ADCC against autologous target cells, and that this educational advantage is maintained after stimulation with function-conferring cytokines, such as IL-15. Furthermore, allelic combinations of KIR3DL1/HLA-Bw4 that are protective in the context of HIV are shown to confer the highest ADCC functional potential. These data suggest that the education of NK cells by allelic combinations of KIR3DL1/HLA-Bw4 could explain some of the protection observed in individuals with these combined genotypes. However, as we also observed anabrogation of this education-conferred functional advantage in HIV-infected individuals, we propose that the mechanisms of NK cell-mediated protection differ between uninfected HESN and infected SP.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,003 | 0,004 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,003 |
| Communication savante | 0,003 | 0,005 |
| Science ouverte | 0,002 | 0,001 |
| Intégrité de la recherche | 0,004 | 0,010 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».