A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses

Abstract

Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses and how such functions are regulated at the molecular level. Here, we identify and characterize a discrete population of CD49a+CD16− NK cells in the human liver that displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16− NK cells when compared with conventional CD49a−CD16+ NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49a+CD16− NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.

Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction

“…Thus far, antigen-specific memory responses mediated by NK cells in humans have been described in VZV-experienced adults 18 as well as in HBV-infected or HAV/HBV-vaccinated individuals 19,20 . While the idea of primate NK cell memory has become well-accepted among immunologists, until now there have been no reported mechanisms describing how NK cells recognize and distinguish individual antigens.…”

“…The interest in harnessing NK cell functions for vaccine design and therapeutic interventions against these pathogens has dramatically increased in recent years, largely driven by a series of observations indicating subpopulations of NK cells, called memory or adaptive NK cells, manifest multiple different forms of durable adaptive capabilities [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . This includes reports of true antigen-specific memory NK cells 5,7,8,10,13,14,[18][19][20] that can mediate recall responses against multiple infectious agents including HIV 7,13,18 and influenza 7,14 . Adaptive NK cell subsets have been associated with protective effects in people living with HIV (PLWH) [21][22][23][24] and exposure to influenza antigens induces protective influenza-specific memory NK cells in mouse models 7,14 .…”

“…To date, only a few studies support the existence of true antigen-specific recall responses by NK cells in humans, which have been described against cytomegalovirus (CMV), varicella zoster virus (VZV), hepatitis A (HAV) and B (HBV) virus and bacillus Calmette-Guerin 15,[18][19][20]25,26 and the opacity surrounding the mechanisms of memory NK cell formation represents a major obstacle to harnessing adaptive NK cell functions. Herein, we provide proof that antigen-specific NK cell memory develops upon exposure to HIV and influenza in humans, and also provide the first mechanistic evidence for memory NK cell recognition of target antigens at the single-cell and single-peptide level.…”

Regulation of the human NK cell compartment by pathogens and vaccines

“…50,51 NK cells with characteristics of liver-resident NK cells (CD56 high CXCR6 + CD16 + NKG2D + CD69 + CD62L + ) were enriched in skin blisters after challenge with VZV skin test antigen, 50 and CD49a + CD16 À human liver NK cells acquire epigenetic modifications and migrate to the skin after hepatitis B vaccination. 51 Hantavirus infection leads to rapid and persistent in vivo expansion of NK cells across the differentiation spectrum including CD57 + NKG2C + NK cells. 52 Such expansions are associated with elevated levels of IL-15 and with the Hantavirusdriven upregulation of HLA-E on infected cells.…”

“…The importance of infection in promoting activation of relatively undifferentiated, tissue‐resident NK cells and migration to distinct anatomical sites is also evident in recall responses to VZV and hepatitis B viruses 50,51 . NK cells with characteristics of liver‐resident NK cells (CD56 high CXCR6 + CD16 + NKG2D + CD69 + CD62L + ) were enriched in skin blisters after challenge with VZV skin test antigen, 50 and CD49α + CD16 − human liver NK cells acquire epigenetic modifications and migrate to the skin after hepatitis B vaccination 51 …”