hla class i molecules
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2021 ◽  
Vol 22 (24) ◽  
pp. 13554
Author(s):  
Caitlin Boyne ◽  
Debra Lennox ◽  
Olivia Beech ◽  
Simon J. Powis ◽  
Pankaj Kumar

The Human Leukocyte Antigen class I (HLA-I) system is an essential part of the immune system that is fundamental to the successful activation of cytotoxic lymphocytes, and an effective subsequent immune attack against both pathogen-infected and cancer cells. The importance of cytotoxic T cell activity and ability to detect foreign cancer-related antigenic peptides has recently been highlighted by the successful application of monoclonal antibody-based checkpoint inhibitors as novel immune therapies. Thus, there is an increased interest in fully characterising the repertoire of peptides that are being presented to cytotoxic CD8+ T cells by cancer cells. However, HLA-I is also known to be present on the surface of extracellular vesicles, which are released by most if not all cancer cells. Whilst the peptide ligandome presented by cell surface HLA class I molecules on cancer cells has been studied extensively, the ligandome of extracellular vesicles remains relatively poorly defined. Here, we will describe the current understanding of the HLA-I peptide ligandome and its role on cancer-derived extracellular vesicles, and evaluate the aspects of the system that have the potential to advance immune-based therapeutic approaches for the effective treatment of cancer.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Benjamin Obando ◽  
Arthur Cross-Najafi ◽  
Kevin Lopez ◽  
Deepthi Thadasina ◽  
Wenjun Zhang ◽  
...  

Background:   Pig-to-human xenotransplantation (XTx) is a promising solution to the organ shortage. Genetically engineered pigs lacking major xenoantigens have reduced hyperacute rejection and prolonged xenograft survival. Despite these advancements, acute xenograft rejection (AXR) remains a major barrier to clinical XTx. AXR is mediated by multiple immune cells, of which natural killer (NK) cells play a crucial role. Previous studies have shown that human HLA-E suppresses NK cell activation through the inhibitory receptor NKG2A. We seek to improve pig-to-human compatibility by expressing HLA-E in a genetically modified pig endothelial cell (pEC) line. This cell line 5GKO/ HLA-G+ has mutations in five genes encoding for xenoantigens and expresses HLA-G, an inhibitory ligand of the NK cell receptor KIR2DL4. In this study, the 5GKO/HLA-G+/HLA-E+ pEC line was established to examine whether co-expression of inhibitory ligands promotes NK cell tolerance.      Methods:   The HLA-Eα/pCDNA3.1 plasmid containing the HLA-E α-chain (HLA-Eα) cDNA driven by a CMV promoter was linearized and introduced into 106 cells of the 5GKO/HLA-G+ pEC line by electroporation. After 48 hours, HLA-E expression was analyzed by flow cytometry. HLA-E+ pECs were isolated by flow cytometry sort and co-cultured with human peripheral blood mononuclear cells (PBMCs) stimulated by IL-2. NK cell degranulation was compared between the 5GKO/HLA-G+ and 5GKO/HLA-G+/HLA-E+ pEC lines by measuring CD107a expression in the CD3- CD56+ cell population.          Results:   HLA-E molecules were successfully expressed on the pECs surface, indicating the HLA-E a chain can pair with the existing b2-microglobulin (B2M). The transfection efficiency was 38.2%. Three weeks later, the 5GKO/HLA-G+/HLA-E+ pEC was successfully established, confirming via flow cytometric analysis. The analysis of NK cell degranulation (CD107a) is underway.     Conclusion:   We established a 5GKO/HLA-G+/HLA-E+ pEC line, which is a valuable tool to study human-to-pig xenoreactive immune response in vitro, with the goal of improving pig-to-human xenograft immunotolerance. 


2021 ◽  
Vol 12 ◽  
Author(s):  
Baimei Zhuang ◽  
Jin Shang ◽  
Yuanqing Yao

Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.


2021 ◽  
Vol 21 ◽  
Author(s):  
Jutaro Nakamura ◽  
Masaki Takeuchi ◽  
Masao Ota ◽  
Nobuhisa Mizuki ◽  
Shigeaki Ohno

: Immune tolerance is established in the eye to prevent permanent blindness associated with destructive damage to the cornea and retina caused by immune cell infiltration; hence, the immune responses and subsequent inflammations are strongly suppressed. While non-infectious uveitis develops from a disruption of immune tolerance in the eye, its onset is a result of accumulating etiologic factors, including genetic predisposition, environmental factors, and aging. Many non-infectious uveitis cases are genetically predisposed to human leukocyte antigen (HLA) as the most substantial disease susceptibility region. HLA class I molecules are critical for natural killer (NK) cells to distinguish between self and non-self. The killer cell Ig-like receptor (KIR) family is one of the essential components of these receptors. Evidence has accumulated that NK cells are involved in innate and acquired immunity by interacting with other immunocompetent cells to develop several autoimmune diseases. This review summarizes the possible role of KIR in the development of non-infectious uveitis.


2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A1.2-A2
Author(s):  
MA Garcia-Marquez ◽  
M Thelen ◽  
E Bauer ◽  
K Wennhold ◽  
J Lehmann ◽  
...  

BackgroundClassical human leukocyte antigen (HLA) class I molecules are expressed by most somatic cells and present peptides to cytotoxic T cells. The HLA-genotype of an individual contains up to six different HLA-I molecules and defines the repertoire of peptides that can be presented to cytotoxic T cells. Homozygosity for one or more HLA-loci could translate in a smaller repertoire of tumour neoantigens possibly presented to cytotoxic T cells in an individual and potentially predispose such individuals with a disadvantage to fight a nascent tumour.Material and MethodsHigh-resolution HLA-genotyping from germline normal DNA of 80 esophago-gastric adenocarcinoma (EGA) patients was performed with the NGS method by Illumina. Whole exome sequencing (WES) was performed on tumor tissue and normal peripheral blood cells (n=39). The data were processed, and non-synonymous mutations were called. The amount of potential high-affinity binders derived from 10 cancer testis antigens (CTAs) frequently expressed in EGA and non-synonymous mutations obtained from WES data were determined using an in-silico approach for MHC-binding (IEDB.org). RNA-extraction and gene expression profiling were performed using the NanoString technology.ResultsWe compared the frequency of HLA homozygosity in EGA patients to an HLA-matched reference population derived from a large cohort of bone marrow donors (n=7.615 out of 615.017 donors). We demonstrate that EGA patients are more likely to be homozygous for at least one HLA-I gene than the control population. In EGA patients, 35% of HLA-A, -B, and -C alleles were homozygous in comparison with 19% of HLA alleles among the HLA-matched general population. This difference corresponded to an odds ratio (OR) for homozygosity of 2.282 (95% confidence interval (CI) 1.442-3.615, p<0.001). The odds ratios for homozygosity at HLA-A (OR=1.885, CI=1.111-3.236, p<0.05), HLA-B (OR=3.045, CI=1.346-6.499, p<0.05) and HLA-C (OR=2.170, CI=1.445-3.579, p<0.05) were significantly different. We then aimed to estimate the influence of HLA-homozygosity in the context of tumour immune surveillance. Predictions by IEDB analysis resource tool indeed showed a reduced repertoire of high and moderate-affinity MHC-binders (both CTA-derived and mutation-derived peptides) in the homozygous cohort. Our findings demonstrate a reduced amount of potentially immunogenic peptides in EGA patients with HLA-homozygosity for at least one locus, which may result in impaired cancer immunosurveillance. In line with this observation, we also found increased levels of CTA expression in homozygous compared to heterozygous patients. After artificial modification of the genotype of homozygous patients to a heterozygous genotype, the set of predicted good-binding peptides was comparable to the heterozygous cohort.ConclusionOur results highlight the effect of HLA-I homozygosity on the immunopeptidome as important prerequisite of anti-tumor immunity. The high frequency of genomic HLA-I homozygosity observed in the EGA cohort may reflect an increased cancer risk for these patients. Together with previous reports demonstrating reduced survival after checkpoint therapy, our study suggests consideration of germ-line HLA-homozygosity for the design and interpretation of immunotherapeutic trials.Disclosure InformationM.A. Garcia-Marquez: None. M. Thelen: None. E. Bauer: None. K. Wennhold: None. J. Lehmann: None. D. Keller: None. B. Gathof: None. L. Maas: None. J. George: None. C. Bruns: None. A. Quaas: None. M. von Bergwelt-Baildon: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; Astellas, Roche, MSD. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Modest; BMS. M. Peifer: None. H.A. Schlößer: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Astra Zeneca. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Modest; BMS.


2021 ◽  
Vol 22 (19) ◽  
pp. 10503
Author(s):  
Elena Lorente ◽  
Miguel Marcilla ◽  
Patricia G. de la Sota ◽  
Adriana Quijada-Freire ◽  
Carmen Mir ◽  
...  

Identification of a natural human leukocyte antigen (HLA) ligandome is a key element to understand the cellular immune response. Advanced high throughput mass spectrometry analyses identify a relevant, but not complete, fraction of the many tens of thousands of self-peptides generated by antigen processing in live cells. In infected cells, in addition to this complex HLA ligandome, a minority of peptides from degradation of the few proteins encoded by the viral genome are also bound to HLA class I molecules. In this study, the standard immunopeptidomics strategy was modified to include the classical acid stripping treatment after virus infection to enrich the HLA ligandome in virus ligands. Complexes of HLA-B*27:05-bound peptide pools were isolated from vaccinia virus (VACV)-infected cells treated with acid stripping after virus infection. The HLA class I ligandome was identified using high throughput mass spectrometry analyses, yielding 37 and 51 natural peptides processed and presented untreated and after acid stripping treatment VACV-infected human cells, respectively. Most of these virus ligands were identified in both conditions, but exclusive VACV ligands detected by mass spectrometry detected on acid stripping treatment doubled the number of those identified in the untreated VACV-infected condition. Theoretical binding affinity prediction of the VACV HLA-B*27:05 ligands and acute antiviral T cell response characterization in the HLA transgenic mice model showed no differences between HLA ligands identified under the two conditions: untreated and under acid stripping condition. These findings indicated that acid stripping treatment could be useful to identify HLA class I ligands from virus-infected cells.


Author(s):  
Andrea T. Nguyen ◽  
Christopher Szeto ◽  
Stephanie Gras

Human leukocyte antigens (HLA) are cell-surface proteins that present peptides to T cells. These peptides are bound within the peptide binding cleft of HLA, and together as a complex, are recognised by T cells using their specialised T cell receptors. Within the cleft, the peptide residue side chains bind into distinct pockets. These pockets ultimately determine the specificity of peptide binding. As HLAs are the most polymorphic molecules in humans, amino acid variants in each binding pocket influences the peptide repertoire that can be presented on the cell surface. Here, we review each of the 6 HLA binding pockets of HLA class I (HLA-I) molecules. The binding specificity of pockets B and F are strong determinants of peptide binding and have been used to classify HLA into supertypes, a useful tool to predict peptide binding to a given HLA. Over the years, peptide binding prediction has also become more reliable by using binding affinity and mass spectrometry data. Crystal structures of peptide-bound HLA molecules provide a means to interrogate the interactions between binding pockets and peptide residue side chains. We find that most of the bound peptides from these structures conform to binding motifs determined from prediction software and examine outliers to learn how these HLAs are stabilised from a structural perspective.


2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Boni ◽  
Davide Cavazzini ◽  
Angelo Bolchi ◽  
Marzia Rossi ◽  
Andrea Vecchi ◽  
...  

There is an urgent need for new generation anti-SARS-Cov-2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading. The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses. This analysis revealed variable levels of cross-neutralization capacity for presently available SARS-Cov-2 vaccines. Despite the dampened immune responses documented for some SARS-Cov-2 mutations, available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern (VoC). This may be attributed, at least in part, to cell-mediated immunity. Indeed, the widely multi-specific nature of CD8 T cell responses should allow to avoid VoC-mediated viral escape, because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co-existing CD8 epitopes. This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS-Cov-2 regions that cannot mutate without impairing SARS-Cov-2 functionality. Importantly, some of these conserved epitopes are degenerate, meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction. Based on these concepts, vaccination strategies aimed at potentiating the stimulatory effect on SARS-Cov-2-specific CD8 T cells should greatly enhance the efficacy of immunization against SARS-Cov-2 variants. Our review recollects, discusses and puts into a translational perspective all available experimental data supporting these “hot” concepts, with special emphasis on the structural constraints that limit SARS-CoV-2 S-protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next-generation, CD8 T-cell response-reinforced, COVID-19 vaccines.


2021 ◽  
Vol 12 ◽  
Author(s):  
Roberto Castro-Gutierrez ◽  
Aimon Alkanani ◽  
Clayton E. Mathews ◽  
Aaron Michels ◽  
Holger A. Russ

Type 1 diabetes results from an autoimmune attack directed at pancreatic beta cells predominantly mediated by T cells. Transplantation of stem cell derived beta-like cells (sBC) have been shown to rescue diabetes in preclinical animal models. However, how sBC will respond to an inflammatory environment with diabetogenic T cells in a strict human setting has not been determined. This is due to the lack of model systems that closely recapitulates human T1D. Here, we present a reliable in vitro assay to measure autologous CD8 T cell stimulation against sBC in a human setting. Our data shows that upon pro-inflammatory cytokine exposure, sBC upregulate Human Leukocyte Antigen (HLA) class I molecules which allows for their recognition by diabetogenic CD8 T cells. To protect sBC from this immune recognition, we utilized genome engineering to delete surface expression of HLA class I molecules and to integrate an inducible overexpression system for the immune checkpoint inhibitor Programmed Death Ligand 1 (PD-L1). Genetically engineered sBC that lack HLA surface expression or overexpress PD-L1 showed reduced stimulation of diabetogenic CD8 T cells when compared to unmodified cells. Here, we present evidence that manipulation of HLA class I and PD-L1 receptors on sBC can provide protection from diabetes-specific immune recognition in a human setting.


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