Between Innate and Adaptive Immune Responses: NKG2A, NKG2C, and CD8+ T Cell Recognition of HLA-E Restricted Self-Peptides Acquired in the Absence of HLA-Ia

Pump, Wiebke C.; Kraemer, Thomas; Huyton, Trevor; Hò, Gia-Gia T; Blasczyk, Rainer; Bade‐Doeding, Christina

doi:10.3390/ijms20061454

Cited by 7 publications

(11 citation statements)

References 59 publications

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“…The recombinant sHLA-G molecules used as capture proteins in this study are bound to a diversity of peptides [66]. Since we could previously show that the interaction of pHLA-E:NKG2A/CD94 and pHLA-E:NKG2C/CD94 is highly dependent on the peptide that is presented by HLA-E [68]; it is unclear if the binding of HLA-G to NKG2A/CD94 might be peptide-dictated as well. However, HLA-G:NKG2A/CD94 engagement could be clearly ascertained, while binding of HLA-G to NKG2C/CD94 could not be detected using LCR-TriCEPS technology or binding experiments using sNKG2C/CD94.…”

Section: Discussionmentioning

confidence: 97%

“…Non-classical HLA molecules act as ligands for the innate immune system and are known to be oligomorphic. However, the invariable non-classical HLA molecule HLA-E has been shown to interact with receptors of the innate immune system in a competing manner depending on the sequence of the presented peptide [23,68]. Whether the engagement of NKG2A/CD94 and HLA-G is dictated by the bound peptide remains to be unraveled since this receptor engages peptide-specific with HLA-E [46,69].…”

Section: Discussionmentioning

confidence: 99%

“…The method used for cloning of a vector encoding for sNKG2A/CD94 and sNKG2C/CD94 heterodimers is described by Pump et al [68]. Constructs encoding for sNKG2A/CD94 or sNKG2C/CD94 with V5-His-tag were cloned into the lentiviral vector pRRL.PPT.SFFV.mcs.pre.…”

Section: Cloning Of Plasmid Encoding For Soluble Nkg2/cd94 Heterodimersmentioning

confidence: 99%

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NKG2A/CD94 Is a New Immune Receptor for HLA-G and Distinguishes Amino Acid Differences in the HLA-G Heavy Chain

Hò

Celik

Huyton

et al. 2020

IJMS

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Natural killer (NK) cell therapies are a tool to antagonize a dysfunctional immune system. NK cells recognize malignant cells, traffic to a tumor location, and infiltrate the solid tumor. The immune checkpoint molecule human leukocyte antigen (HLA)-G is upregulated on malignant cells but not on healthy surrounding cells, the requirement of understanding the basis of receptor mediated events at the HLA-G/NK cell interface becomes obvious. The NK cell receptors ILT2 and KIR2DL4 have been described to bind to HLA-G; however, their differential function and expression levels on NK cell subsets suggest the existence of an unreported receptor. Here, we performed a ligand-based receptor capture on living cells utilizing sHLA-G*01:01 molecules coupled to TriCEPS and bound to NK cells followed by mass spectrometric analyses. We could define NKG2A/CD94 as a cognate receptor of HLA-G. To verify the results, we used the reciprocal method by expressing recombinant soluble heterodimeric NKG2A/CD94 molecules and used them to target HLA-G*01:01 expressing cells. NKG2A/CD94 could be confirmed as an immune receptor of HLA-G*01:01. Despite HLA-G is marginal polymorphic, we could previously demonstrate that the most common allelic subtypes HLA-G*01:01/01:03 and 01:04 differ in peptide repertoire, their engagement to NK cells, their catalyzation of dNK cell proliferation and their impact on NK cell development. Continuing these studies with regard to NKG2A/CD94 engagement we engineered recombinant single antigen presenting K562 cells and targeted the surface expressed HLA-G*01:01, 01:03 or 01:04 molecules with NKG2A/CD94. Specificity and sensitivity of HLA-G*01:04/NKG2A/CD94 engagement could be significantly verified. The binding affinity decreases when using K562-G*01:03 or K562-G*01:01 cells as targets. These results demonstrate that the ligand-receptor assignment between HLA-G and NKG2A/CD94 is dependent of the amino acid composition in the HLA-G heavy chain. Understanding the biophysical basis of receptor-mediated events that lead to NK cell inhibition would help to remove non-tumor reactive cells and support personalized mild autologous NK cell therapies.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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NKG2A/CD94 Is a New Immune Receptor for HLA-G and Distinguishes Amino Acid Differences in the HLA-G Heavy Chain

Hò

Celik

Huyton

et al. 2020

IJMS

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“…CD8 + T cells express on their surfaces inhibitory receptor NKG2A, and, in higher extent, activatory NKG2C receptor [41]. Nevertheless, they are able to recognize complexes of HLA-E with peptides, also via αβTCR as an activatory receptor.…”

Section: Hla-e-peptide Complexes and Tcrmentioning

confidence: 99%

Dimorphism of HLA-E and Its Disease Association

Kanevskiy

Erokhina

Kobyzeva

et al. 2019

IJMS

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HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER, HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.

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“…Expression of HLA-E on the cell surface avoids the recognition of HLA-Ia empty and viral infected cells by NK cells [33] through HLA-E-NKG2A interaction. The interaction between HLA-E is allele- [16] and peptide- [15,34] specific; therefore, the selection of NKG2A-ligated HLA-E-peptides is the key to pathogenic immune escape or immune survival. The same holds true for HLA-G function, a molecule that confers protection to the fetus from the maternal immune system during pregnancy [35].…”

Section: Discussionmentioning

confidence: 99%

HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint

Hò

Heinen

Blasczyk

et al. 2019

IJMS

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Peptide-dependent engagement between human leucocyte antigens class I (HLA-I) molecules and their cognate receptors has been extensively analyzed. HLA-F belongs to the non-classical HLA-Ib molecules with marginal polymorphic nature and tissue restricted distribution. The three common allelic variants HLA-F*01:01/01:03/01:04 are distinguished by polymorphism outside the peptide binding pockets (residue 50, α1 or residue 251, α3) and are therefore not considered relevant for attention. However, peptide selection and presentation undergoes a most elaborated extraction from the whole available proteome. It is known that HLA-F confers a beneficial effect on disease outcome during HIV-1 infections. The interaction with the NK cell receptor initiates an antiviral downstream immune response and lead to delayed disease progression. During the time of HIV infection, HLA-F expression is upregulated, while its interaction with KIR3DS1 is diminished. The non-polymorphic nature of HLA-F facilitates the conclusion that understanding HLA-F peptide selection and presentation is essential to a comprehensive understanding of this dynamic immune response. Utilizing soluble HLA technology we recovered stable pHLA-F*01:01, 01:03 and 01:04 complexes from K562 cells and analyzed the peptides presented. Utilizing a sophisticated LC-MS-method, we analyzed the complete K562 proteome and matched the peptides presented by the respective HLA-F subtypes with detected proteins. All peptides featured a length of 8 to 24 amino acids and are not N-terminally anchored; the C-terminus is preferably anchored by Lys. To comprehend the alteration of the pHLA-F surface we structurally compared HLA-F variants bound to selected peptides. The peptides were selected from the same cellular content; however, no overlap between the proteomic source of F*01:01, 01:03 or 01:04 selected peptides could be observed. Recognizing the balance between HLA-F expression, HLA-F polymorphism and peptide selection will support to understand the role of HLA-F in viral pathogenesis.

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Between Innate and Adaptive Immune Responses: NKG2A, NKG2C, and CD8+ T Cell Recognition of HLA-E Restricted Self-Peptides Acquired in the Absence of HLA-Ia

Cited by 7 publications

References 59 publications

NKG2A/CD94 Is a New Immune Receptor for HLA-G and Distinguishes Amino Acid Differences in the HLA-G Heavy Chain

NKG2A/CD94 Is a New Immune Receptor for HLA-G and Distinguishes Amino Acid Differences in the HLA-G Heavy Chain

Dimorphism of HLA-E and Its Disease Association

HLA-F Allele-Specific Peptide Restriction Represents an Exceptional Proteomic Footprint

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