scholarly journals Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide

2004 ◽  
Vol 199 (2) ◽  
pp. 271-281 ◽  
Author(s):  
Martin Hülsmeyer ◽  
Maria Teresa Fiorillo ◽  
Francesca Bettosini ◽  
Rosa Sorrentino ◽  
Wolfram Saenger ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Salt Bridge ◽  
Binding Mode ◽  
Histocompatibility Antigens ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
Peptide Binding Groove ◽  
Major Histocompatibility Antigens ◽  
Binding Groove

The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not. The subtypes also generate differential T cell repertoires as exemplified by distinct T cell responses against the self-peptide pVIPR (RRKWRRWHL). The crystal structures described here show that pVIPR binds in an unprecedented dual conformation only to HLA-B*2705 molecules. In one binding mode, peptide pArg5 forms a salt bridge to Asp116, connected with drastically different interactions between peptide and heavy chain, contrasting with the second, conventional conformation, which is exclusively found in the case of B*2709. These subtype-dependent differences in pVIPR binding link the emergence of dissimilar T cell repertoires in individuals with HLA-B*2705 or HLA-B*2709 to the buried Asp116/His116 polymorphism and provide novel insights into peptide presentation by major histocompatibility antigens.

scholarly journals Unravelling the Proteomics of HLA-B*57:01+ Antigen Presenting Cells during Abacavir Medication

2022 ◽  
Vol 12 (1) ◽  
pp. 40
Author(s):  
Funmilola Josephine Haukamp ◽  
Eline Gall ◽  
Gia-Gia Toni Hò ◽  
Wiebke Hiemisch ◽  
Florian Stieglitz ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Antigen Presenting Cells ◽  
Type B ◽  
Leukocyte Antigen ◽  
Hiv Therapy ◽  
Cell Mediated Immune Response ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Antigen Presenting

Type B adverse drug reactions (ADRs) are unpredictable based on the drug’s pharmacology and represent a key challenge in pharmacovigilance. For human leukocyte antigen (HLA)-mediated type B ADRs, it is assumed that the protein/small-molecule interaction alters the biophysical and mechanistic properties of the antigen presenting cells. Sophisticated methods enabled the molecular appreciation of HLA-mediated ADRs; in several instances, the drug molecule occupies part of the HLA peptide binding groove and modifies the recruited peptide repertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal of medication. The severe ADR in HLA-B*57:01+ patients treated with the antiretroviral drug abacavir (ABC) in anti-HIV therapy is an example of HLA-drug-T cell cooperation. However, the long-term damages of the HLA-B*57:01-expressing immune cells following ABC treatment remain unexplained. Utilizing full proteome sequencing following ABC treatment of HLA-B*57:01+ cells, we demonstrate stringent proteomic alteration of the HLA/drug presenting cells. The proteomic content indisputably reflects the cellular condition; this knowledge directs towards individual pharmacovigilance for the development of personalized and safe medication.

scholarly journals Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 403
Author(s):  
Insu Jeon ◽  
Jeong-Mi Lee ◽  
Kwang-Soo Shin ◽  
Taeseung Kang ◽  
Myung Hwan Park ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Growth Factor Receptor ◽  
Human Leukocyte ◽  
T Cell Responses ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
Her2 Antigen

For cancer vaccines, the selection of optimal tumor-associated antigens (TAAs) that can maximize the immunogenicity of the vaccine without causing unwanted adverse effects is challenging. In this study, we developed two engineered Human epidermal growth factor receptor 2 (HER2) antigens, K965 and K1117, and compared their immunogenicity to a previously reported truncated HER2 antigen, K684, within a B cell and monocyte-based vaccine (BVAC). We found that BVAC-K965 and BVAC-K1117 induced comparable antigen-specific antibody responses and antigen-specific T cell responses to BVAC-K684. Interestingly, BVAC-K1117 induced more potent antitumor activity than the other vaccines in murine CT26-HER2 tumor models. In addition, BVAC-K1117 showed enhanced antitumor effects against truncated p95HER2-expressing CT26 tumors compared to BVAC-K965 and BVAC-K684 based on the survival analysis by inducing T cell responses against intracellular domain (ICD) epitopes. The increased ICD epitope-specific T cell responses induced by BVAC-K1117 compared to BVAC-K965 and BVAC-K684 were recapitulated in human leukocyte antigen (HLA)-untyped human PBMCs and HLA-A*0201 PBMCs. Furthermore, we also observed synergistic antitumor effects between BVAC-K1117 and anti-PD-L1 antibody treatment against CT26-HER2 tumors. Collectively, our findings demonstrate that inclusion of a sufficient number of ICD epitopes of HER2 in cellular vaccines can improve the antitumor activity of the vaccine and provide a way to optimize the efficacy of anticancer cellular vaccines targeting HER2.

scholarly journals Machine Learning-Enhanced T Cell Neoepitope Discovery for Immunotherapy Design

2019 ◽  
Vol 18 ◽  
pp. 117693511985208 ◽  
Author(s):  
Joana Martins ◽  
Carlos Magalhães ◽  
Miguel Rocha ◽  
Nuno S Osório
Keyword(s):  
Machine Learning ◽  
T Cell ◽  
Human Leukocyte ◽  
Quality Analysis ◽  
T Cell Epitopes ◽  
Fully Integrated ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
Peptide Interaction ◽  
Peptide Binding Affinity

Immune responses mediated by T cells are aimed at specific peptides, designated T cell epitopes, that are recognized when bound to human leukocyte antigen (HLA) molecules. The HLA genes are remarkably polymorphic in the human population allowing a broad and fine-tuned capacity to bind a wide array of peptide sequences. Polymorphisms might generate neoepitopes by impacting the HLA-peptide interaction and potentially alter the level and type of generated T cell responses. Multiple algorithms and tools based on machine learning (ML) have been implemented and are able to predict HLA-peptide binding affinity with considerable accuracy. Challenges in this field include the availability of adequate epitope datasets for training and benchmarking and the development of fully integrated pipelines going from next-generation sequencing to neoepitope prediction and quality analysis metrics. Effectively predicting neoepitopes from in silico data is a demanding task that has been facilitated by ML and will be of great value for the future of personalized immunotherapies against cancer and other diseases.

scholarly journals Designing Peptide-Based HIV Vaccine for Chinese

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Jiayi Shu ◽  
Xiaojuan Fan ◽  
Jie Ping ◽  
Xia Jin ◽  
Pei Hao
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Hiv Vaccine ◽  
Cd4 T Cell ◽  
Cell Vaccine ◽  
Vaccine Research ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
T Cell Vaccine ◽  
Hla Dr

CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese.

scholarly journals The Molecular and Functional Characteristics of HLA-G and the Interaction with Its Receptors: Where to Intervene for Cancer Immunotherapy?

2020 ◽  
Vol 21 (22) ◽  
pp. 8678
Author(s):  
Jiji V. D. Attia ◽  
Charlotte E. Dessens ◽  
Ricky van de Water ◽  
Ruben D. Houvast ◽  
Peter J. K. Kuppen ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Promote Tumor Growth ◽  
Peptide Binding Groove ◽  
Binding Groove ◽  
Human Leukocyte Antigen G

Human leukocyte antigen G (HLA-G) mediates maternal-fetal immune tolerance. It is also considered an immune checkpoint in cancer since it may mediate immune evasion and thus promote tumor growth. HLA-G is, therefore, a potential target for immunotherapy. However, existing monoclonal antibodies directed against HLA-G lack sufficient specificity and are not suitable for immune checkpoint inhibition in a clinical setting. For this reason, it is essential that alternative approaches are explored to block the interaction between HLA-G and its receptors. In this review, we discuss the structure and peptide presentation of HLA-G, and its interaction with the receptors Ig-like transcript (ILT) 2, ILT4, and Killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4). Based on our findings, we propose three alternative strategies to block the interaction between HLA-G and its receptors in cancer immunotherapy: (1) prevention of HLA-G dimerization, (2) targeting the peptide-binding groove of HLA-G, and (3) targeting the HLA-G receptors. These strategies should be an important focus of future studies that aim to develop immune checkpoint inhibitors to block the interaction between HLA-G and its receptors for the treatment of cancer.

Association of human leukocyte antigen and T cell message with human papillomavirus 16–positive cervical neoplasia in Japanese women

2007 ◽  
Vol 17 (6) ◽  
pp. 1314-1321 ◽  
Author(s):  
M. Saito ◽  
M. Okubo ◽  
R. Hirata ◽  
S. Takeda ◽  
H. Maeda
Keyword(s):  
Human Papillomavirus ◽  
T Cell ◽  
Mhc Class Ii ◽  
Human Leukocyte ◽  
Class Ii ◽  
Cervical Neoplasia ◽  
Hpv 16 ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
Cin Iii

To investigate whether an association exists between human leukocyte antigen (HLA) haplotype and cervical neoplasia within the Japanese population, we analyzed the human papillomavirus (HPV) genotypes, the HLA class I specificities and class II alleles, and the T-cell responses in the lesions of patients with cervical neoplasia. Eighty-one patients, consisting of 62 cervical intraepithelial neoplasia (CIN) lesions and 19 invasive cervical cancers (ICC), were examined. The frequencies of HPV infection in the CIN I/II and CIN III/ICC groups were 68.0% (17/25) and 80.4% (45/56), respectively. All patients and 138 local Japanese controls were analyzed for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1. For major histocompatibility complex (MHC) class II HLA-DRB1 alleles, the frequency of DRB1*0901 was significantly elevated in HPV 16–positive CIN III/ICC patients compared with controls (59.3% versus 29.7%, P= 0.0031, OR = 3.44). Similarly for the HLA-DQB1 alleles, a significant increase in the DQB1*03032 frequency was observed in HPV 16–positive CIN III/ICC patients compared with controls (59.3% versus 28.3%, P= 0.0018, OR = 3.69). In the analysis of the T-cell responses in the lesions, Fas ligand was detected at a decreased frequency in HPV 16–positive CIN III/ICC patients with the HLA-DRB1*0901–DQB1*03032 haplotype. The presence of helper T cell–specific messenger RNAs in the cervical lesions supports an association among MHC class II, helper T cells, the immune response to HPV, and the development of cervical carcinoma. Accordingly, a specific MHC class II haplotype, DRB1*0901–DQB1*03032, may be a risk factor for cervical carcinoma in the Japanese population.

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