Stable Frequencies of HLA-C*03:04/Peptide-Binding KIR2DL2/3+ Natural Killer Cells Following Vaccination.

Maja Christiane Ziegler,Wilfredo F Garcia-Beltran,Sebastian Lunemann,Christian Hoffmann,Julian Schulze Zur Wiesch,Anne Rechtien,Marcus Altfeld,Ferran Borràs Grañana

doi:10.3389/fimmu.2018.02361

Abstract

Inhibitory KIRs play a central role in regulating NK cell activity. KIR2DL2/3 bind to HLA-C molecules, but the modulation of these interactions by viral infections and presentation of viral epitopes is not well-understood. We investigated whether the frequencies of KIR2DL2/3+ NK cells recognizing HLA-C*03:04/viral peptide complexes were impacted by YFV vaccination or HIV-1 and HCV infection. Ex vivo HLA class I tetramer staining of primary human NK cells derived from YFV-vaccinated individuals, or HIV-1- or HCV-infected individuals revealed that the YFV/HLA-C*03:04-NS2A4−13-tetramer bound to a larger proportion of KIR2DL2/3+ NK cells compared to HIV-1/HLA-C*03:04-Gag296−304- or HCV/HLA-C*03:04-Core136−144-tetramers. The YFV/HLA-C*03:04-NS2A4−13-tetramer also exhibited a stronger avidity to KIR2DL2/3 compared to the other tested tetramers. The proportional frequencies of KIR2DL2/3+ NK cells binding to the three tested HLA-C*03:04 tetramers were identical between YFV-vaccinated individuals or HIV-1- or HCV-infected individuals, and remained stable following YFV vaccination. These data demonstrate consistent hierarchies in the frequency of primary KIR2DL2/3+ NK cells binding HLA-C*03:04/peptide complexes that were determined by the HLA-C-presented peptide and not modulated by the underlying viral infection or vaccination.

Highlights

Natural killer (NK) cells are an important component of the innate immune system and play a critical role in the early control of infections and malignancies
HLA-C tetramers have been previously reported to bind to primary human NK cells [18], but it remains unknown whether the frequencies of HLA-C tetramer-binding KIR2DL2/3+ NK cells change during viral infections or are influenced by antigen-exposure
To investigate whether frequencies of KIR2DL2/3+ NK cells binding to HLA-C∗03:04 molecules presenting these peptides differ in Yellow Fever Virus (YFV) vaccine recipients or HIV-1- and HCV-infected individuals, we used HLA-C∗03:04 tetramers refolded with the respective peptides as a tool to ex vivo stain primary human NK cells of YFV-vaccinated (28 days post vaccination), HIV-1-infected or HCV-infected individuals (Table 1)

Summary

Introduction

Natural killer (NK) cells are an important component of the innate immune system and play a critical role in the early control of infections and malignancies. Function of NK cells is regulated through a balanced interplay between activating and inhibitory receptors. One of the major receptor families modulating NK cell function is the group of killer-cell immunoglobulin-like receptors (KIRs), which interact with HLA-I molecules expressed on nucleated cells [2]. KIRs contain either two or three immunoglobulin-like domains in the extracellular region, and are named as KIR2D or KIR3D receptors. KIRs exhibiting a short cytoplasmic tail deliver an activating signal upon stimulation through interaction with the adaptor molecule DAP-12. Inhibitory KIRs possess a long cytoplasmic tail containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and prevent NK cell activation after ligand binding [3]. Several epidemiological studies have shown that expression of specific KIRs can be beneficial in the context of viral infections, especially when expressed in combination with their respective HLA-I ligands. The combination of KIR2DL3 and HLA-C alleles of the HLA-C group 1 (HLA-C1) was associated with spontaneous clearance of HCV infection [4, 5]

Methods

Results

Conclusion