Dynamic Interaction between Immune Escape Mechanism and HLA-Ib Regulation

Hò, Gia-Gia T; Heinen, Funmilola J.; Stieglitz, Florian; Blasczyk, Rainer; Bade‐Doeding, Christina

doi:10.5772/intechopen.80731

Cited by 5 publications

(3 citation statements)

References 148 publications

(193 reference statements)

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“…The human leukocyte antigen (HLA) complex, which is located within a 3.6-Mbp stretch on the short arm of chromosome 6 (6q21.31), can encode the human major histocompatibility complex (MHC) proteins and play a key role in adaptive and innate immunity [ 1 , 2 ]. It can be divided into two categories: HLA-I (HLA-Ia, Ib) genes encode MHC-I proteins presenting in all nucleated cells and can bind to intracellular antigens for cell destruction through CD8+ cytotoxic T cells [ 3 ];HLA-II (HLA-DP, −DQ,-DR) genes encode MHC-II proteins existing in the antigen-presenting cells and can recognize intracellular and extracellular antigens for antibody production via CD4+ helper T cells. As is known, the HLA system includes the most polymorphic genes with marked differences in allele frequency between and within ethnic groups.…”

Section: Introductionmentioning

confidence: 99%

Investigations of sequencing data and sample type on HLA class Ia typing with different computational tools

Yi¹,

Chen²,

Xiao³

et al. 2020

Briefings in Bioinformatics

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Human leukocyte antigen (HLA) can encode the human major histocompatibility complex (MHC) proteins and play a key role in adaptive and innate immunity. Emerging clinical evidences suggest that the presentation of tumor neoantigens and neoantigen-specific T cell response associated with MHC class I molecules are of key importance to activate the adaptive immune systemin cancer immunotherapy. Therefore, accurate HLA typing is very essential for the clinical application of immunotherapy. In this study, we conducted performance evaluations of 4 widely used HLA typing tools (OptiType, Phlat, Polysolver and seq2hla) for predicting HLA class Ia genes from WES and RNA-seq data of 28 cancer patients. HLA genotyping data using PCR-SBT method was firstly obtained as the golden standard and was subsequently compared with HLA typing data by using NGS techniques. For both WES data and RNA-seq data, OptiType showed the highest accuracy for HLA-Ia typing than the other 3 programs at 2-digit and 4-digit resolution. Additionally, HLA typing accuracy from WES data was higher than from RNA-seq data (99.11% for WES data versus 96.42% for RNA-seq data). The accuracy of HLA-Ia typing by OptiType can reach 100% with the average depth of HLA gene regions >20x. Besides, the accuracy of 2-digit and 4-digit HLA-Ia typing based on control samples was higher than tumor tissues. In conclusion, OptiType by using WES data from control samples with the high average depth (>20x) of HLA gene regions can present a probably superior performance for HLA-Ia typing, enabling its application in cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

Investigations of sequencing data and sample type on HLA class Ia typing with different computational tools

Yi¹,

Chen²,

Xiao³

et al. 2020

Briefings in Bioinformatics

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“…Consequently, infected cells do not present pH LA-Ia complexes on the surface and would be susceptible to NK cell-mediated lysis [12]. Non-classical HLA-Ib molecules are upregulated during these infectious periods and protect HLA-Ia empty cells from being recognized by NK cells [33]. Distinct pHLA-E complexes are stabilized on the cell surface and provide a ligand for inhibitory NKG2A/CD94 receptor.…”

Section: Discussionmentioning

confidence: 99%

The Loss of HLA-F/KIR3DS1 Ligation Is Mediated by Hemoglobin Peptides

Hò

Hiemisch

Pich

et al. 2020

IJMS

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The human leukocyte antigen (HLA)-Ib molecule, HLA-F, is known as a CD4+ T-cell protein and mediator of HIV progression. While HLA-Ia molecules do not have the chance to select and present viral peptides for immune recognition due to protein downregulation, HLA-F is upregulated. Post HIV infection, HLA-F loses the affinity to its activating receptor KIR3DS1 on NK cells leading to progression of the HIV infection. Several studies aimed to solve the question of the biophysical interface between HLA ligands and their cognate receptors. It became clear that even an invariant HLA molecule can be structurally modified by the variability of the bound peptide. We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA (sHLA) technology and a sophisticated MS method. We established recombinant K562 cells that express membrane-bound HLA-F*01:01, 01:03 or 01:04 complexes. While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased. We used CD4+/HIV− and CD4+/HIV+ cells and performed an MS proteome analysis. We could detect hemoglobin as significantly upregulated in CD4+ T-cells post HIV infection. The expression of cellular hemoglobin in nonerythroid cells has been described, yet HLA-Ib presentation of hemoglobin-derived peptides is novel. Peptide sequence analysis from HLA-F allelic variants featured hemoglobin peptides as dominant and shared. The reciprocal experiment of binding hemoglobin peptide fractions to the HLA-F open conformers resulted in significantly diminished receptor recognition. These results underpin the molecular involvement of HLA-F and its designated peptide ligand in HIV immune escape.

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“…HLA-Ib molecules play a role as part of immune evasion strategies and/or are mediators of immune tolerance and are therefore characterized by their restricted tissue distribution [13]. Despite their marginal polymorphic nature and proposed immunological invariability, most HLA-Ib allelic variants differ substantially in their peptide profiles [14,15,16]; this variability results in differential immune responses [17,18].…”

Section: Introductionmentioning

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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Dynamic Interaction between Immune Escape Mechanism and HLA-Ib Regulation

Cited by 5 publications

References 148 publications

Investigations of sequencing data and sample type on HLA class Ia typing with different computational tools

Investigations of sequencing data and sample type on HLA class Ia typing with different computational tools

The Loss of HLA-F/KIR3DS1 Ligation Is Mediated by Hemoglobin Peptides

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

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