Distinct HLA-E Peptide Complexes Modify Antibody-Driven Effector Functions of Adaptive NK Cells

Rölle, Alexander; Meyer, Marten; Calderazzo, Silvia; Jäger, Dirk; Momburg, Frank

doi:10.1016/j.celrep.2018.07.069

Cited by 74 publications

(114 citation statements)

References 63 publications

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“…Recently it was demonstrated that HCMV-derived peptides presented by HLA-E, in particular the rare UL40 peptide VMAPRTLFL which is identical to the HLA-G leader peptide, fine tune the ADCC response of NK cells via NKG2C recognition (17). Both membrane bound and soluble levels of HLA-G are reported to be increased in untreated HIV infection and during HCMV infection and have been shown to correlate with blood IFN-γ concentrations and could therefore represent a source of HLA-E peptides in T/T individuals (29) (30) (31).…”

Section: Resultsmentioning

confidence: 99%

“…In keeping with this, we observed a range of ADCC responses in our cohort that correlated with NKG2C expression. Furthermore, UL40 in HCMV encodes peptides that mimic MHC class I signal sequences and share a conserved methionine (M) anchor residue at peptide amino-acid residue 2), which correspond to amino acid −21 of the classical HLA class I leader sequence (16) (17). Hence HCMV infection provides peptides that may substitute for host HLA-I-derived HLA-E stabilising nonameric peptides in T/T donors.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly UL40 polymorphisms and the strength of interactions between HLA-E presented peptide and NKG2C controls the activation of adaptive NK cells. Of note, a gradient in NKG2C+ NK cell effector function has been reported depending on the potency of recognition of HCMV peptides (VMAPRTLFL > VMAPRTLIL > VMAPRTLVL) (17). The VMAPRTLFL UL40 derived peptide mimics the signal peptide of HLA-G, the expression of which is upregulated during inflammation, HCMV infection and HIV-1 infection, and specifically enhances antibody-driven adaptive NK cell responses as recently described (17).…”

Section: Discussionmentioning

confidence: 99%

“…We have recently demonstrated the potent effect of HCMV co-infection in shaping the NK cell repertoire during chronic HIV-1 infection, leading to an accelerated differentiation and adaptive reconfiguration of the NK cell compartment and expansion of an NK cell subset expressing NKG2C, the activating counterpart of NKG2A that also binds to HLA-E (recognizing HLA-E bound to HLA class la signal sequence peptides with lower affinity than NKG2A) (13) (14) (15). The relevance of HLA-E/NKG2C interactions has been well demonstrated in driving adaptive NK cell expansions and more recently a highly specific recognition of certain HCMV-encoded HLA-E presented peptides was elegantly shown (16) (17). A rare UL40 peptide, identical to the HLA-E-binding peptide in the HLA-G signal sequence, was found to trigger optimal NK stimulation and to have functional consequences, influencing NK cell antibody dependent cellular cytotoxicity (ADCC) responses(17).…”

Section: Introductionmentioning

confidence: 99%

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Subordinate effect of −21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin

Cubero

Ogbe

Cohen

et al. 2019

Preprint

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Natural Killer (NK) cells play an important role in antiviral defence and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position −21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, −21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of NK cells in a cohort of African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position −21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and −C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV/HCMV coinfection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B −21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with −21M HLA-B alleles. Instead our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Subordinate effect of −21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin

Cubero

Ogbe

Cohen

et al. 2019

Preprint

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“…In particular HCMV co-infection, a hallmark of HIV-1 infected cohorts, triggers a dramatic expansion of differentiated NK cells expressing the activating receptor NKG2C, which prototypically characterises adaptive NK cells (Guma et al, 2006) (Mela and Goodier, 2007) (Brunetta et al, 2010). These expanded NKG2C+ NK cells co-express CD57, a marker of maturation, and are influenced by HLA-E presented peptides (Hammer et al, 2018) (Rolle et al, 2018). Notably they resemble memory CD8 T cells and are imbued with enhanced capacity for antibody dependent cellular cytotoxicity (ADCC), in particular increased IFN-γ production attributed to epigenetic remodelling of the IFNG locus (Schlums et al, 2015) (Lee et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Cubero

Balint

Alrubayyi³

et al. 2019

Preprint

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16Dynamic regulation of cellular metabolism is important for maintaining homeostasis and can directly 17 influence immune cell function and differentiation including Natural Killer (NK) cell responses. 18Persistent HIV-1 infection leads to a state of chronic activation, subset redistribution and progressive 45 et al., 2015) (Lee et al., 2015). The adaptive reconfiguration of NK cells during HIV-1 infection is further 46 delineated by loss of the transcription factor promyelocytic leukaemia zinc finger protein (PLZF), and 47 downstream signalling molecules such as FcεRI-γ (Peppa et al., 2018), which partly overlap with 48 NKG2C expression. While these attributes are considered important in the functional specialisation of 49 2 these NK cells, the development of these features under conditions of continuous 50 stimulation/persistent inflammation during HIV-1 infection could lead to the establishment of 51 functionally and metabolically exhausted NK cells akin to exhausted CD8 T cells. In keeping with this 52 notion, chronic stimulation of adaptive NK cells through NKG2C ligation was recently found to lead to 53 a molecular programme of exhaustion that is shared between NK cells and CD8 T cells (Merino et al., 54 2019). Exhausted CD8 T cells are characterised by a number of metabolic defects, however, to date it 55 remains unexplored how persistent HIV-1 infection contributes to the metabolic remodelling of NK 56 cell subsets. NK cell exhaustion could influence responses to CD16 engagement linked to vaccine-57 induced protective immunity against HIV-1 infection and phenotypes of viral control (Scully and Alter, 58 2016). Such knowledge represents a critical first step in our understanding of the metabolic machinery 59 of NK cell subsets with distinct immunologic features that can be potentially targeted for developing 60 new or complementary antiviral approaches aimed at enhancing ADCC responses. 61 62 Whereas metabolic regulation of T cell function is well characterised, evidence of the importance of 63 immunometabolism in facilitating robust NK cell functions is gradually emerging. Notably, impaired 64 NK cell cellular metabolism has been implicated in obesity and cancer, providing a new framework for 65 understanding NK cell functionality (Michelet et al., 2018) (Cong et al., 2018). Studies from both 66 human and murine models have demonstrated that NK cells activated through cytokine stimulation 67 exhibit substantial increases in the rates of both glycolysis and oxidative phosphorylation (OXPHOS) 68 pathways (Marcais et al., 2014) (Donnelly et al., 2014) (Keating et al., 2016; O'Brien and Finlay, 2019). 69However, the metabolic requirement of NK cells for optimal effector function, in terms of IFN- 70 production, depends on the specific activation stimuli. In particular, receptor mediated activation 71 through anti-NK1.1 and anti-Ly49D in mice appears to require OXPHOS as an essential second signal 72 for IFN- production and appears more susceptible to metabolic inhibition compared to cytokine 73 stimulation ...

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Human NK cells, their receptors and function

et al. 2021

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NK cells are cytotoxic components of innate lymphoid cells (ILC) that provide a first line of defense against viral infections and contribute to control tumor growth and metastasis. Their function is finely regulated by an array of HLA‐specific and non‐HLA‐specific inhibitory and activating receptors which allow to discriminate between healthy and altered cells. Human NK cells gained a major attention in recent years because of the important progresses in understanding their biology and of some promising data in tumor therapy. In this review, we will outline well‐established issues of human NK cells and discuss some of the open questions, debates, and recent advances regarding their origin, differentiation, and tissue distribution. Newly defined NK cell specializations, including the impact of inhibitory checkpoints on their function, their crosstalk with other cell types, and the remarkable adaptive features acquired in response to certain virus infections will also be discussed.

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Distinct HLA-E Peptide Complexes Modify Antibody-Driven Effector Functions of Adaptive NK Cells

Cited by 74 publications

References 63 publications

Subordinate effect of −21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin

Subordinate effect of −21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin

IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection

Human NK cells, their receptors and function

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