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 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 A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease

2020 ◽  
Vol 117 (6) ◽  
pp. 3063-3073 ◽  
Author(s):  
Yi Tian Ting ◽  
Shiva Dahal-Koirala ◽  
Hui Shi Keshia Kim ◽  
Shuo-Wang Qiao ◽  
Ralf S. Neumann ◽  
...  
Keyword(s):  
Celiac Disease ◽  
T Cell ◽  
Molecular Basis ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
T Cell Response ◽  
Leukocyte Antigen ◽  
Disease Penetrance ◽  
Polymorphic Residue ◽  
Antigen Presenting

The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4+ T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5–mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance.

scholarly journals Antigen identification for HLA class I– and HLA class II–restricted T cell receptors using cytokine-capturing antigen-presenting cells

2021 ◽  
Vol 6 (55) ◽  
pp. eabf4001
Author(s):  
Mark N. Lee ◽  
Matthew Meyerson
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Leukocyte ◽  
Antigen Presenting Cells ◽  
Hla Class I ◽  
Class Ii ◽  
Class I ◽  
Identification System ◽  
Antigen Presenting

A major limitation to understanding the associations of human leukocyte antigen (HLA) and CD8+ and CD4+ T cell receptor (TCR) genes with disease pathophysiology is the technological barrier of identifying which HLA molecules, epitopes, and TCRs form functional complexes. Here, we present a high-throughput epitope identification system that combines capture of T cell–secreted cytokines by barcoded antigen-presenting cells (APCs), cell sorting, and next-generation sequencing to identify class I– and class II–restricted epitopes starting from highly complex peptide-encoding oligonucleotide pools. We engineered APCs to express anti-cytokine antibodies, a library of DNA-encoded peptides, and multiple HLA class I or II molecules. We demonstrate that these engineered APCs link T cell activation–dependent cytokines with the DNA that encodes the presented peptide. We validated this technology by showing that we could select known targets of viral epitope–, neoepitope-, and autoimmune epitope–specific TCRs, starting from mixtures of peptide-encoding oligonucleotides. Then, starting from 10 TCRβ sequences that are found commonly in humans but lack known targets, we identified seven CD8+ or CD4+ TCR-targeted epitopes encoded by the human cytomegalovirus (CMV) genome. These included known epitopes, as well as a class I and a class II CMV epitope that have not been previously described. Thus, our cytokine capture–based assay makes use of a signal secreted by both CD8+ and CD4+ T cells and allows pooled screening of thousands of encoded peptides to enable epitope discovery for orphan TCRs. Our technology may enable identification of HLA-epitope-TCR complexes relevant to disease control, etiology, or treatment.

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.

scholarly journals Cord-Blood-Derived Professional Antigen-Presenting Cells: Functions and Applications in Current and Prospective Cell Therapies

2021 ◽  
Vol 22 (11) ◽  
pp. 5923
Author(s):  
Sarah Cunningham ◽  
Holger Hackstein
Keyword(s):  
Cord Blood ◽  
Human Leukocyte ◽  
Antigen Presenting Cells ◽  
Lymphoid Cells ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Hematopoietic Stem ◽  
Cell Therapies ◽  
Leukocyte Antigen ◽  
Antigen Presenting

Human umbilical cord blood (UCB) represents a valuable source of hematopoietic stem cells, particularly for patients lacking a matching donor. UCB provides practical advantages, including a lower risk of graft-versus-host-disease and permissive human leukocyte antigen mismatching. These advantageous properties have so far been applied for stem cell, mesenchymal stromal cell, and chimeric antigen receptor T cell therapies. However, UCB-derived professional antigen-presenting cells are increasingly being utilized in the context of immune tolerance and regenerative therapy. Here, we review the cell-specific characteristics as well as recent advancements in UCB-based cell therapies focusing on dendritic cells, monocytes, B lymphocytes, innate lymphoid cells, and macrophages.

Duvelisib as bridge to allotransplantation in refractory peripheral T-cell lymphoma with T-follicular helper phenotype: case report

2021 ◽  
pp. 030089162110272
Author(s):  
Ginevra Lolli ◽  
Beatrice Casadei ◽  
Cinzia Pellegrini ◽  
Lisa Argnani ◽  
Federica Cocito ◽  
...  
Keyword(s):  
Case Report ◽  
T Cell ◽  
Human Leukocyte ◽  
Complete Response ◽  
Unrelated Donor ◽  
Phosphatidylinositol 3 Kinase ◽  
Leukocyte Antigen ◽  
Follicular Helper ◽  
T Cell Lymphomas ◽  
T Cell Malignancies

Objective: Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous T-cell malignancies representing 5%–10% of aggressive lymphomas. The prognosis is poor for patients with relapsed/refractory (R/R) disease, with a median overall survival of less than 6 months and no standardized treatments. We discuss the role of the phosphatidylinositol 3-kinase (PI3K) γδ inhibitor duvelisib as bridge to allotransplantation in a patient with R/R PTCL. Methods: Case report. Results: A 55-year-old woman diagnosed with relapsed nodal PTCL with T-follicular helper phenotype received PI3K γδ inhibitor duvelisib in the context of the phase II PRIMO clinical trial. After two cycles at a dose of 75 mg twice daily, the patient achieved complete response (CR), which was subsequently consolidated with human leukocyte antigen fully matched unrelated donor allotransplantation. No major toxicities were recorded during the duvelisib treatment period or during hospitalization for allotransplantation. At the latest follow-up, the patient was alive and still in CR 10 months posttransplant. Conclusions: Duvelisib should be further explored as a bridge to allotransplantation in patients with R/R PTCL, given the success and low toxicity in our patient.

T Cells: A Growing Universe of Roles in Neurodegenerative Diseases

2021 ◽  
pp. 107385842110249
Author(s):  
Dallin Dressman ◽  
Wassim Elyaman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neurodegenerative Diseases ◽  
Human Leukocyte ◽  
Autoimmune Response ◽  
Antigen Specificity ◽  
Risk Genes ◽  
Leukocyte Antigen ◽  
Histocompatibility Complex ◽  
The Central Nervous System

T cells play a central role in homeostasis and host defense against infectious diseases. T cell dysregulation can lead to recognizing self-antigens as foreign antigens, causing a detrimental autoimmune response. T cell involvement in multiple sclerosis (MS), long understood to be an autoimmune-mediated neurodegenerative disease, is well characterized. More recently, a role for T cells has also been identified for the neurodegenerative diseases Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Interestingly, several alleles and variants of human leukocyte antigen (HLA) genes have been classified as AD and PD risk genes. HLA codes for components of major histocompatibility complex (MHC) class I or class II, both of which are expressed by microglia, the innate immune cells of the central nervous system (CNS). Thus, both microglia and T cells may potentially interact in an antigen-dependent or independent fashion to shape the inflammatory cascade occurring in neurodegenerative diseases. Dissecting the antigen specificity of T cells may lead to new options for disease-modifying treatments in neurodegenerative diseases. Here, we review the current understanding of T cells in neurodegenerative diseases. We summarize the subsets of T cells, their phenotype and potential functions in animal models and in human studies of neurodegenerative diseases.

scholarly journals A conserved energetic footprint underpins recognition of human leukocyte antigen-E by two distinct αβ T cell receptors

2017 ◽  
Vol 292 (51) ◽  
pp. 21149-21158 ◽  
Author(s):  
Lucy C. Sullivan ◽  
Nicholas G. Walpole ◽  
Carine Farenc ◽  
Gabriella Pietra ◽  
Matthew J. W. Sum ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte Antigen ◽  
T Cell Receptors ◽  
Human Leukocyte ◽  
Cell Receptors ◽  
Leukocyte Antigen
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