Differential Impact of HLA-B*44 Allelic Mismaches at Position 156 on Peptide Binding Specificities and T-Cell Diversity

Badrinath, S; Huyton, Trevor; Kunze‐Schumacher, Heike; Elsner, Holger A.; Blasczyk, Rainer; Doeding, Christina Bade

doi:10.4172/2157-7633.1000192

Cited by 4 publications

(2 citation statements)

References 22 publications

(31 reference statements)

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“…1 , HLA-E*01:03 exhibits a strong preference for Lys at the pΩ position and as such may be less variable in the F-pocket than E*01:01. The unusual selection of Lys as an anchor is similar to HLA-B*44:35 that presents longer peptides preferentially anchored by Lys at the C-terminus (Badrinath et al 2014 ). This restriction of the pΩ anchor (Fig.…”

Section: Discussionmentioning

confidence: 99%

The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch

et al. 2015

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Human leukocyte antigen (HLA)-E molecules are potent inhibitors of NK cell-mediated killing. Low in polymorphisms, two alleles are widely expressed among diverse populations: HLA-E*01:01 and HLA-E*01:03. Both alleles are distinguished by one SNP resulting in the substitution Arg107Gly. Both alleles present a limited set of peptides derived from class I leader sequences physiologically; however, HLA-E*01:01 presents non-canonical peptides in the absence of HLA class I molecules. To further assess the functional differences between both alleles, we analyzed the peptide repertoire of HLA-E*01:03 by applying soluble HLA technology followed by mass-spectrometric peptide sequencing. HLA-E*01:03 restricted peptides showed a length of 9–17 amino acids and differed in their biophysical properties, no overlap in the peptide repertoire of both allelic variants could be observed; however, both alleles shared marginal peptides from the same proteomic content. Artificial APCs expressing empty HLA-E*01:01 or E*01:03 molecules were generated and stabilized using cognate HLA class I-derived peptide ligands to analyze the impact of residue 107 within the HLA-E heavy chain on the NKG2/CD94 receptor engagement. Differences in peptide stabilization could be translated to the density and half-life time of peptide-HLA-E molecules on the cell surface that subsequently impacted NK cell inhibition as verified by cytotoxicity assays. Taken together, these data illustrate functional differences of HLA-E allelic variants induced by a single amino acid. Furthermore, the function of HLA-E in pathophysiologic situations when the HLA processing machinery is interrupted seems to be more emphasized than previously described, implying a crucial role for HLA-E in tumor or viral immune episodes.

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Section: Discussionmentioning

confidence: 99%

The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch

et al. 2015

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“…The allelic variants B*44:02 Asp156 and B*44:35 Glu156 differ at a single mismatch; both of the AAs exchanged are polar acidic and thus not expected to confer alteration of the PBR feature. However, the comparison of the peptides from B*44:02 Asp156 and B*44:35 Glu156 showed an unexpected alteration in the binding motif of the peptide's pΩ [ 34 ]. B*44:35 Glu156 was found to bind and present a significantly high number of peptides of extraordinary length and to disfavour the binding and presentation of canonical peptides.…”

Section: Determination Of Mismatch Impact Based On Peptide Sequencmentioning

confidence: 99%

Soluble HLA Technology as a Strategy to Evaluate the Impact of HLA Mismatches

Kunze‐Schumacher

Blasczyk

Bade‐Doeding

2014

Journal of Immunology Research

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HLA class I incompatibilities still remain one of the main barriers for unrelated bone marrow transplantation (BMT); hence the molecular understanding of how to mismatch patients and donors and still have successful clinical outcomes will guide towards the future of unrelated BMT. One way to estimate the magnitude of polymorphisms within the PBR is to determine which peptides can be selected by individual HLA alleles and subsequently presented for recognition by T cells. The features (structure, length, and sequence) of different peptides each confer an individual pHLA landscape and thus directly shape the individual immune response. The elution and sequencing of peptides by mass spectrometric analysis enable determining the bona fide repertoire of presented peptides for a given allele. This is an effective and simple way to compare the functions of allelic variants and make a first assessment of their degree of permissivity. We describe the methodology used for peptide sequencing and the limitations of peptide prediction tools compared to experimental methods. We highlight the altered peptide features that are observed between allelic variants and the need to discover the altered peptide repertoire in situations of “artificial” graft versus host disease (GvHD) that occur in HLA-specific hypersensitive immune responses to drugs.

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Understanding the obstacle of incompatibility at residue 156 within HLA-B*35 subtypes

et al. 2016

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Defining permissive and non-permissive mismatches for transplantation is a demanding challenge. Single mismatches at amino acid (AA) position 156 of human leucocyte antigen (HLA) class I have been described to alter the peptide motif, repertoire, or mode of peptide loading through differential interaction with the peptide-loading complex. Hence, a single mismatch can tip the balance and trigger an immunological reaction. HLA-B*35 subtypes have been described to evade the loading complex, 156 mismatch distinguishing B*35:01 and B*35:08 changes the binding groove sufficiently to alter the sequence features of the selected peptide repertoire. To understand the functional influences of residue 156 in B*35 variants, we analyzed the peptide binding profiles of HLA-B*35:01156Leu, B*35:08156Arg and B*35:62156Trp. The glycoprotein tapasin represents a target for immune evasions and functions within the multimeric peptide-loading complex to stabilize empty class I molecules and promote acquisition of high-affinity peptides. All three B*35 subtypes showed a tapasin-independent mode of peptide acquisition. HLA-B*35-restricted peptides of low- and high-binding affinities were recovered in the presence and absence of tapasin and subsequently sequenced utilizing mass spectrometry. The peptides derived from B*35 variants differ substantially in their features dependent on their mode of recruitment; all peptides were preferentially anchored by Pro at p2 and Tyr, Phe, Leu, or Lys at pΩ. However, the Trp at residue 156 altered the p2 motif to an Ala and restricted the pΩ to a Trp. Our results highlight the importance of understanding the impact of key micropolymorphism and how a single AA mismatch orchestrates the neighboring AAs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-015-0896-4) contains supplementary material, which is available to authorized users.

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Differential Impact of HLA-B*44 Allelic Mismaches at Position 156 on Peptide Binding Specificities and T-Cell Diversity

Cited by 4 publications

References 22 publications

The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch

The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch

Soluble HLA Technology as a Strategy to Evaluate the Impact of HLA Mismatches

Understanding the obstacle of incompatibility at residue 156 within HLA-B*35 subtypes

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