Critical Role of CD2 Co-stimulation in Adaptive Natural Killer Cell Responses Revealed in NKG2C-Deficient Humans.

Lisa L Liu,Stella Larsson,Monika Enqvist,Kjetil Taskén,Jyothi Jayaraman,Ebba Sohlberg,Hans-Gustaf Ljunggren,Vincent Y.S Oei,James A Traherne,Chiara Romagnani,John Trowsdale,Vivien Béziat,Jodie P Goodridge,Eivind H Ask,Karl-Johan Malmberg,Johannes Landskron,Marie Schaffer,Quirin Hammer

doi:10.1016/j.celrep.2016.04.005

Abstract

SummaryInfection by human cytomegalovirus (HCMV) leads to NKG2C-driven expansion of adaptive natural killer (NK) cells, contributing to host defense. However, approximately 4% of all humans carry a homozygous deletion of the gene that encodes NKG2C (NKG2C−/−). Assessment of NK cell repertoires in 60 NKG2C−/− donors revealed a broad range of NK cell populations displaying characteristic footprints of adaptive NK cells, including a terminally differentiated phenotype, functional reprogramming, and epigenetic remodeling of the interferon (IFN)-γ promoter. We found that both NKG2C− and NKG2C+ adaptive NK cells expressed high levels of CD2, which synergistically enhanced ERK and S6RP phosphorylation following CD16 ligation. Notably, CD2 co-stimulation was critical for the ability of adaptive NK cells to respond to antibody-coated target cells. These results reveal an unexpected redundancy in the human NK cell response to HCMV and suggest that CD2 provides “signal 2” in antibody-driven adaptive NK cell responses.

Highlights

Human cytomegalovirus (HCMV) is a persistent betaherpes virus with a worldwide prevalence ranging between 50% and 100% of the population depending on socioeconomic factors
Minimal Imprint in T Cell Immunity in Individuals Carrying Homozygous Deletion of NKG2C The absence of more severe HCMV infection in NKG2CÀ/À donors indicates the existence of redundant pathways for the control of the infection
We analyzed the impact of homozygous NKG2C deletion on the differentiation profile and the anti-HCMV response of CD4 and CD8 T cells from NKG2CÀ/À donors as compared to NKG2C+ (NKG2C+/+ or NKG2C+/À) donors (Figures 1, S1, and S2)

Summary

Introduction

Human cytomegalovirus (HCMV) is a persistent betaherpes virus with a worldwide prevalence ranging between 50% and 100% of the population depending on socioeconomic factors. Recent advances in NK cell biology suggest that NK cells display adaptive features during CMV infection, contributing to viral control (Vivier et al, 2011). Unlike T and B cell immune responses, CMV-driven adaptive NK cell responses do not rely on receptor rearrangement. Infection with mouse CMV (MCMV) leads to a clonal expansion of NK cells expressing the activating receptor Ly49H, which binds to the MCMV-encoded protein m157 (Arase et al, 2002). Optimal differentiation of adaptive Ly49H+ NK cells depends on delivery of ‘‘signal 2,’’ provided through co-stimulation via DNAM-1 (Nabekura et al, 2014). The expansion and contraction within the Ly49H+ NK cell population result in a pool of memory NK cells that mediate long-lasting protection against subsequent challenges with the virus (Sun et al, 2009)

Results

Discussion

Conclusion