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Titel: Effect of HLA class I-peptides on KIR+ NK cell function in the context of viral infections
Sonstige Titel: Einfluss von HLA-Klasse-I-Peptiden auf die Funktion von KIR+ NK-Zellen im Kontext von viralen Infektionen
Sprache: Englisch
Autor*in: Chapel, Anais
Schlagwörter: NK-Zellen; Innate Immunity; NK cells; HIV-1; HCV
GND-Schlagwörter: Immunologie; HIV; Hepatitis
Erscheinungsdatum: 2017
Tag der mündlichen Prüfung: 2017-12-08
Zusammenfassung: 
Background & Aims: NK cells play an important role in viral infection and distinct KIR/HLA associations have shown to influence viral disease outcome, in particular for HCV and HIV-1 infection. Viral infections are able to alter the repertoire of peptides presented by HLA class I molecules and thereby impact KIR/HLA interactions. We aim to identify HLA/peptide complexes binding to the inhibitory NK cell receptor KIR2DL3 and the activating NK cell receptor KIR2DS1 to gain a better understanding of how HLA class I-ligands modulate KIR binding and thus influence NK cell functions.

Methods: To investigate the influence of peptides presented by the HLA-C on KIR2DL3 and KIR2DS1 binding, we established reporter cell assays which measure the response of KIR2DL3-IgG fusion construct to peptide-pulsed 721.221.TAP1ICP47-HLA-C*03:04 cells and KIR2DS1-transfected Jurkat cells to peptide-pulsed 721.221.TAP1KO-HLA-C*06:02 cells. These assays were used to screen a large panel of HCV, HIV-1 virus-derived and synthetic peptides. Primary NK cells and NK cell clones were isolated from healthy donors to investigate how the peptides identified impacted KIR2DL3+ and KIR2DS1+ NK cell function.

Results: One HCV peptide “YIPLVGAPL” was identified to induce strong binding of KIR2DL3 to 721.221.HLA-C*03:04 cells and inhibited KIR2DL3+ NK cell function. This sequence exhibited a high frequency of mutations in different HCV genotypes and point mutations on the peptide showed lower ability to inhibit KIR2DL3+ NK cell function. On the contrary, one synthetic HLA-C*06:02-presented peptide, “SRGPVHHLL”, was identified to induce strong binding of KIR2DS1 and increase the activation of primary KIR2DS1+ NK cell clones. No peptide virus-derived was identified binding to KIR2DS1.

Conclusions: We successfully identified novel HLA/peptide complexes as ligands for KIR2DL3 and KIR2DS1 and confirmed that HLA class I peptides impact KIR+ NK cell functions. Our results suggest that one HCV derived HLA class I peptide can impact KIR2DL3+ NK cell functions and that naturally occurring sequence mutations in the peptide alter these interaction making the inhibition less efficient, providing potential pathways for viral escape. On the other hand, we confirmed the peptide-dependent binding of the activating NK cell receptor KIR2DS1 and our results suggested that an additional factor might be required to induce effective in vivo KIR2DS1+ NK cell function.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/7506
URN: urn:nbn:de:gbv:18-89176
Dokumenttyp: Dissertation
Betreuer*in: Altfeld Marcus (Prof. Dr.)
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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