Induction of cytotoxic T-cell responses against immunoglobulin V region–derived peptides modified at human leukocyte antigen–A2 binding residues

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 2999-3005 ◽  
Author(s):  
Sabine Harig ◽  
Mathias Witzens ◽  
Angela M. Krackhardt ◽  
Andreas Trojan ◽  
Patrick Barrett ◽  
...  
Keyword(s):  
Amino Acid ◽  
Human Leukocyte Antigen ◽  
Binding Affinity ◽  
Mhc Class I ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Native Peptide ◽  
Binding Residues ◽  
V Region ◽  
Heteroclitic Peptides

Abstract Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides derived from the immunoglobulin (Ig) V region in some but not all patients. The main reason for this appears to be the low peptide-binding affinity of Ig-derived peptides to major histocompatibility complex (MHC) class I molecules and their resulting low immunogenicity. This might be improved by conservative amino acid modifications at the MHC-binding residues of the peptides (heteroclitic peptides). In this study, it was found that in 18 Ig-derived peptides, that heteroclitic peptides from the Ig gene with improved binding to human leukocyte antigen (HLA)-A*0201 can be used to improve CTL responses. Amino acid substitution substantially increased predicted binding affinity, and there was a strong correlation between predicted and actual binding to HLA-A*0201. CTLs generated against the heteroclitic peptide had not only enhanced cytotoxicity against the heteroclitic peptide but also increased killing of antigen-presenting cells pulsed with the native peptide. Surprisingly, no difference was observed in the frequency of T cells detected by MHC class I peptide tetramers after stimulation with the heteroclitic peptide compared with the native peptide. CTLs generated against heteroclitic peptides could kill patients' tumor cells, showing that Ig-derived peptides can be presented by the tumor cell and that the failure to mount an immune response (among other reasons) likely results from the low immunogenicity of the native Ig-derived peptide. These results suggest that heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting immune responses, and that they might be useful tools for enhancing immunotherapy approaches to treating B-cell malignant diseases.

Successful Generation of Cytotoxic T-Cells That Kill CLL Cells Using Heteroclitic Peptides Is Independent of the Native Peptide Binding Affinity to HLA-A*0201.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 54-54 ◽  
Author(s):  
Katja Mauerer ◽  
Gullu Gorgun ◽  
David Zahrieh ◽  
John G. Gribben
Keyword(s):  
Tumor Cells ◽  
Binding Affinity ◽  
Mhc Class I ◽  
Binding Assay ◽  
Cytotoxic T Cells ◽  
B Cell Malignancies ◽  
Specific Lysis ◽  
Native Peptide ◽  
Native Peptides ◽  
Heteroclitic Peptides

Abstract Targeting immunoglobulin (Ig) framework region (FR) derived peptides offers the advantage of a less patient specific immunotherapeutic strategy in B-cell malignancies. A major limitation of this method is the generally low immunogenicity and low binding affinity of these peptides to MHC class I and class II molecules. Heteroclitic peptide modifications can increase immunogenicity of low binding peptides while leaving T-cell recognition residues intact, and improve ability to generate cytotoxic T cells lines (CTL). It is not known whether such CTLs can still kill tumor cells that express native peptides below a lower threshold of binding affinity. To address this, we sequenced Ig, identified nonameric and decameric peptide sequences that potentially bind to HLA-A*0201 (HLA-A2) that were frequently shared among patients. We used two independent computer prediction analysis tools, determined binding using the T2-binding assay, screened peptide specific CTL responses with an established T-cell expansion system, and assessed cytotoxicity of the CTL lines against native and heteroclitic peptide pulsed APCs and also primary tumor cells from which the native peptides were derived. 34 FR-derived peptides were synthesized, 17 native peptides selected to represent a wide range of predicted binding to HLA-A2, and 17 corresponding heteroclitic counterparts. There was a strong correlation of predicted binding assessed by both scores (Spearmen rho=0.62; p=0.0001) and with respective T2-binding (Spearmen rho=0.66; p<0.0001). Heteroclitic peptides has significantly enhanced predicted binding compared to their native counterparts (Parker Score p<0.00001; Rammensee Score p=0.004, T2-binding p=0.0005) and CTLs generated against heteroclitic peptides had significantly enhanced killing of CD40 activated B-cells pulsed not only with the corresponding heteroclitic peptide (p=0.0003), but also with the native peptide (p=0.04). The binding affinity of low (n=10; FI<0.5) or intermediate binding (n=7; FI>0.6) native peptides did not correlate with specific lysis of peptide pulsed CD40 activated B-cells by CTLs generated against native peptides. Binding affinity of heteroclitic peptides correlated with the ability to induce CTL responses (Spearman rho=0.50; p=0.04). CTLs generated against heteroclitic peptide killed primary CLL cells more effectively than those generated against their native counterparts (p=0.01). Most importantly, the specific lysis of primary tumor cells by successfully generated CTLs was independent of the original binding affinity of the native peptides, both as measured by T2 binding assay (Spearman rho=0.38; p=0.36) and as predicted by the Parker Score (Spearman rho=0.22; p=0.60) or the Rammensee Score (Spearman rho=0.02; p=0.95). Thus, the present study demonstrates recognition of naturally processed Ig-derived peptides even with extremely low binding affinity to MHC class I when higher affinity analogues are used as ‘in vitro’ immunogens. Once CTLs are generated, cytotoxicity appears to be independent of the original binding affinity, suggesting that the rate limiting factor is the ability to generate the immune response, but that once generated, these CTLs have ability to kill tumor cells bearing even very weakly immunogenic peptides. These findings have significant implication for vaccination strategies in B-cell malignancies and warrant in vivo evaluation of this model in CLL.

scholarly journals The human leukocyte antigen (HLA)-C-specific "activatory" or "inhibitory" natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions.

1996 ◽  
Vol 183 (2) ◽  
pp. 645-650 ◽  
Author(s):  
R Biassoni ◽  
C Cantoni ◽  
M Falco ◽  
S Verdiani ◽  
C Bottino ◽  
...  
Keyword(s):  
Amino Acid ◽  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Receptor Activation ◽  
Leukocyte Antigen ◽  
Allele Specificity ◽  
Specific Receptors ◽  
Activation Motif

Natural killer cells express clonally distributed receptors specific for major histocompatibility complex class I molecules. The human leukocyte antigen (HLA)-C-specific receptors have been molecularly identified and cloned. They exist not only as inhibitory (p58) but also as activatory (p50) receptors. Here we show that p50 and p58 are highly homologous in their extracellular regions formed by two Ig-like domains. In contrast, major differences exist in their transmembrane and cytoplasmic portions. Whereas p 58 displays a 76-84-amino acid cytoplasmic tail containing an unusual antigen receptor activation motif, p50 is characterized by a shorter 39-amino acid tail. In addition, whereas p58 has a nonpolar transmembrane portion, p50 contains the charged amino acid Lys. These data strongly suggest that receptors with identical HLA-C allele specificity can mediate functions of opposite sign owing to their different transmembrane/cytoplasmic portions.

scholarly journals Influence of T Cell-Mediated Immune Surveillance on Somatic Mutation Occurrences in Melanoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Chongming Jiang ◽  
Evelien Schaafsma ◽  
Wei Hong ◽  
Yanding Zhao ◽  
Ken Zhu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Mhc Class I ◽  
Somatic Mutations ◽  
Immune Surveillance ◽  
Human Leukocyte ◽  
The Cancer Genome Atlas ◽  
Class I ◽  
Leukocyte Antigen ◽  
Recurrent Mutations ◽  
Cancer Genome Atlas

BackgroundNeoantigens are presented on the cancer cell surface by peptide-restricted human leukocyte antigen (HLA) proteins and can subsequently activate cognate T cells. It has been hypothesized that the observed somatic mutations in tumors are shaped by immunosurveillance.MethodsWe investigated all somatic mutations identified in The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) samples. By applying a computational algorithm, we calculated the binding affinity of the resulting neo-peptides and their corresponding wild-type peptides with the major histocompatibility complex (MHC) Class I complex. We then examined the relationship between binding affinity alterations and mutation frequency.ResultsOur results show that neoantigens derived from recurrent mutations tend to have lower binding affinities with the MHC Class I complex compared to peptides from non-recurrent mutations. Tumor samples harboring recurrent SKCM mutations exhibited lower immune infiltration levels, indicating a relatively colder immune microenvironment.ConclusionsThese results suggested that the occurrences of somatic mutations in melanoma have been shaped by immunosurveillance. Mutations that lead to neoantigens with high MHC class I binding affinity are more likely to be eliminated and thus are less likely to be present in tumors.

scholarly journals Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Austin Nguyen ◽  
Julianne K. David ◽  
Sean K. Maden ◽  
Mary A. Wood ◽  
Benjamin R. Weeder ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Human Leukocyte Antigen ◽  
Mhc Class I ◽  
Human Leukocyte ◽  
Viral Disease ◽  
Hla Typing ◽  
Class I ◽  
Susceptibility Map ◽  
Leukocyte Antigen ◽  
Human Coronaviruses

ABSTRACT Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic. IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.

Human Leukocyte Antigen Class II Amino Acid Epitopes

2002 ◽  
Vol 165 (6) ◽  
pp. 788-794 ◽  
Author(s):  
MILTON D. ROSSMAN ◽  
JOSE STUBBS ◽  
CHUNG WHA LEE ◽  
ELIAS ARGYRIS ◽  
ELENI MAGIRA ◽  
...  
Keyword(s):  
Amino Acid ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte Antigen Class ◽  
Human Leukocyte ◽  
Class Ii ◽  
Leukocyte Antigen

The new human leukocyte antigen-A*2631 is characterized by a new HLA-A polymorphism at amino acid position 62

2006 ◽  
Vol 68 (4) ◽  
pp. 344-345 ◽  
Author(s):  
A. Balas ◽  
F. Sánchez-Gordo ◽  
C. Hernández-Lamas ◽  
F. García-Sánchez ◽  
J. L. Vicario
Keyword(s):  
Amino Acid ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Amino Acid Position ◽  
Leukocyte Antigen ◽  
Antigen A

MHC Class I related chain A (MICA), Human Leukocyte Antigen (HLA)-DRB1, HLA-DQB1 genotypes in Turkish patients with ulcerative colitis

2020 ◽  
Vol 45 (5) ◽  
pp. 587-592
Author(s):  
Cigdem Kekik Cinar ◽  
Kadir Demir ◽  
Sonay Temurhan ◽  
Filiz Akyuz ◽  
Binnur Pinarbasi ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Human Leukocyte Antigen ◽  
Mhc Class I ◽  
Patient Group ◽  
Human Leukocyte ◽  
Class I ◽  
Control Group ◽  
Leukocyte Antigen ◽  
Hla Genotypes ◽  
Turkish Patients

AbstractObjectivesWe aimed to determine Human Leukocyte Antigen (HLA)-DRB1, DQB1, and MHC Class I related chain A (MICA) genotypes in patients with ulcerative colitis.MethodsHLA-DRB1, HLA-DQB1, MICA genotyping of patient (n:85) and controls (n:100) were performed by PCR-SSO Luminex (One Lambda genotyping kit).ResultsWe found significantly higher DRB1*01 (p:0.022, OR:0.23, CI:0.06–0.8) and MICA*0002/20/55 (p:0.03, OR:0.53, CI:0.29–0.93) alleles in control group whereas DRB1*14 (p:0.04, OR:2.25, CI:1–5.08), DRB1*15 (p:<0.0001, OR:4.54, CI:2.09–9.88) and MICA*0004 (p:0.01, OR:2.84, CI:1.2–6.7) alleles were higher in patient group.ConclusionsThe present study will inform the MICA and HLA genotypes about the protective (DRB1*01, MICA*0002/20/55) or susceptible (DRB1*14, DRB1*15, MICA*0004) alleles of the disease and helps the literature on Turkish patients with ulcerative colitis.

scholarly journals SARS-CoV-2 Virus and Human Leukocyte Antigen (HLA) Class II: Investigation in silico of Binding Affinities for COVID-19 Protection and Vaccine Development

2020 ◽  
Vol 4 (4) ◽  
pp. 12-23 ◽  
Author(s):  
Spyros Charonis ◽  
Effie-Photini Tsilibary ◽  
Apostolos Georgopoulos
Keyword(s):  
Human Leukocyte Antigen ◽  
Binding Affinity ◽  
In Silico ◽  
Vaccine Development ◽  
Human Leukocyte ◽  
Class Ii ◽  
Hla Class Ii ◽  
Effective Vaccine ◽  
Binding Affinities ◽  
Leukocyte Antigen

SARS-CoV-2 causes COVID-19, urgently requiring the development of effective vaccine(s). Much of current efforts focus on the SARS-CoV-2 spike-glycoprotein by identifying highly antigenic epitopes as good vaccine candidates. However, high antigenicity is not sufficient, since the activation of relevant T cells depends on the presence of the complex of the antigen with a suitably matching Human Leukocyte Antigen (HLA) Class II molecule, not the antigen alone: in the absence of such a match, even a highly antigenic epitope in vitro will not elicit antibody formation in vivo. Here we assessed systematically in silico the binding affinity of epitopes of the spike-glycoprotein to 66 common HLA-Class-II alleles (frequency ≥ 0.01). We used a sliding epitope window of 22-amino-acid-width to scan the entire protein and determined the binding affinity of each subsequence to each HLA allele. DPB1 had highest binding affinities, followed by DRB1 and DQB1. Higher binding affinities were concentrated in the initial part of the glycoprotein (S1-S460), with a peak at S223-S238. This region would be well suited for effective vaccine development by ensuring high probability for successful matching of the vaccine antigen from that region to a HLA Class II molecule for CD4+ T cell activation by the antigen-HLA molecule complex.

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