Titel: Impact of viral infections on Natural Killer cell frequencies and recognition
Sonstige Titel: Einfluss viraler Infektionen auf Frequenz und Erkennung Natürlicher Killerzellen
Sprache: Englisch
Autor*in: Ziegler, Maja Christiane
Schlagwörter: NK cells; HLA-I; KIR HIV; HCV; viral infection; HLA-I presented peptides
Erscheinungsdatum: 2020
Tag der mündlichen Prüfung: 2020-10-23
Natural killer cells (NK cells) are known to play a crucial role in the control of viral infections. It is described that inhibitory killer cell immunoglobuline-like receptors (KIRs) expressed on NK cells modulate NK cell activity through the binding to human leukocyte antigen class I (HLA-I). These interactions are influenced by viral infections altering intracellular peptide repertoires available for presentation by HLA-I. KIR2DL2/3 binds to HLA-C molecules, but the exact mechanisms how this interaction is modulated by viral infections remains incompletely understood. In the first part of this thesis, I investigated whether frequencies of KIR2DL2/3+ NK cells recognizing HLA-C*03:04/viral peptide complexes are impacted by Yellow Fever Virus vaccination and HIV-1 or HCV infection. Ex vivo HLA-I tetramer staining of primary human NK cells revealed that the proportion of teramer+KIR2DL2/3+ NK cells remained stable over time after antigen exposure and that the avidity of the tetramer to KIR2DL2/3 dictated the frequency of tetramer+KIR2DL2/3+ NK cells. In the second part, I focused on HIV-1-induced alterations in the HLA-I-presented peptide repertoire and how these changes modulate the function of NK cells. Using mass spectrometric analysis, I identified a total of 533 peptides exclusively presented on HIV-1-infected cells, of which only 0.2 % represented HIV-1-derived peptides. Cell-based in vitro assays focusing on HLA-C*03:04/KIR2DL3 interactions revealed that HLA-C*03:04-presented peptides derived from non-infected CD4+ T cells mediated stronger binding of inhibitory KIR2DL3 than peptides derived from HIV-1-infected cells. All in all these data show that interactions between inhibitory KIRs and their HLA-I ligands are modulated by the HLA-presented peptide, but that these interactions do not result in the expansion or accumulation of specific inhibitory KIR+ NK cell subpopulations. But, HIV-1-infection-induced changes in HLA-I-presented peptides can reduce engagement of inhibitory KIRs, providing a mechanism for enhanced activation of NK cells by virus-infected cells leading to a more favorable disease outcome.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/8705
URN: urn:nbn:de:gbv:18-ediss-88293
Dokumenttyp: Dissertation
Betreuer*in: Altfeld, Marcus
Meier, Chris
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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