Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells

ABSTRACTUnderstanding and eliciting protective immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an urgent priority. To facilitate these objectives, we have profiled the repertoire of human leukocyte antigen class II (HLA-II)-bound peptides presented by HLA-DR diverse monocyte-derived dendritic cells pulsed with SARS-CoV-2 spike (S) protein. We identify 209 unique HLA-II-bound peptide sequences, many forming nested sets, which map to sites throughout S including glycosylated regions. Comparison of the glycosylation profile of the S protein to that of the HLA-II-bound S peptides revealed substantial trimming of glycan residues on the latter, likely introduced during antigen processing. Our data also highlight the receptor-binding motif in S1 as a HLA-DR-binding peptide-rich region. Results from this study have application in vaccine design, and will aid analysis of CD4+ T cell responses in infected individuals and vaccine recipients.

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The peptide-binding motif for the human transporter associated with antigen processing.

Journal of Experimental Medicine ◽

10.1084/jem.182.6.1883 ◽

1995 ◽

Vol 182 (6) ◽

pp. 1883-1895 ◽

Cited By ~ 143

Author(s):

P M van Endert ◽

D Riganelli ◽

G Greco ◽

K Fleischhauer ◽

J Sidney ◽

...

Keyword(s):

Human Leukocyte Antigen ◽

Antigen Processing ◽

Human Leukocyte Antigen Class ◽

Human Leukocyte ◽

Class I ◽

Peptide Transport ◽

Binding Motif ◽

Antigenic Peptides ◽

Leukocyte Antigen ◽

Leukocyte Antigen Class I

Presentation of antigenic peptides by human leukocyte antigen class I molecules is dependent on peptide transport into the endoplasmic reticulum by the transporters associated with antigen processing (TAP) (Germain, R. N. 1994. Cell. 76:287-299). This translocation step is currently regarded as permissive for all peptides with COOH-terminal residues capable of binding to HLA class I molecules (Momburg, F., J. Roelse, J. C. Howard, G. W. Butcher, G.J. Hämmerling, and J.J. Neefjes. 1994. Nature (Lond.). 367:648-651). In this report, we show that the human transporter selects peptides according to a binding motif based on the strong effects on peptide affinity of the three NH2-terminal positions and the COOH-terminal residues. TAP favors strongly hydrophobic residues in position 3 (P3) and hydrophobic or charged residues in P2, whereas aromatic or acidic residues in P1, as well as Pro in P1 and P2, have strong deleterious effects. Selection of naturally presented peptides by the transporter is suggested by their higher average affinity for TAP, as compared to nonselected peptides. The TAP preferences in the three NH2-terminal positions correspond to those of the vast majority of human leukocyte antigen class I alleles, but they represent an obstacle for peptide supply to some alleles, e.g., the B7-like group. We propose that peptides binding to these alleles, and in general, peptides with TAP affinities below a certain threshold, may be transported as extended precursors.

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Human histocompatibility leukocyte antigen (HLA)-DM edits peptides presented by HLA-DR according to their ligand binding motifs.

Journal of Experimental Medicine ◽

10.1084/jem.184.5.2019 ◽

1996 ◽

Vol 184 (5) ◽

pp. 2019-2024 ◽

Cited By ~ 90

Author(s):

S M van Ham ◽

U Grüneberg ◽

G Malcherek ◽

I Bröker ◽

A Melms ◽

...

Keyword(s):

Ligand Binding ◽

Mhc Class Ii ◽

Class Ii ◽

Binding Motif ◽

Leukocyte Antigen ◽

Hla Dr ◽

Allele Specific ◽

Natural Peptides ◽

Hla Dr3 ◽

Mhc Class Ii Molecules

Human histocompatibility leukocyte antigen (HLA)-DM is a facilitator of antigen presentation via major histocompatibility complex (MHC) class II molecules. In the absence of HLA-DM, MHC class II molecules do not present natural peptides, but tend to remain associated with class II-associated invariant chain peptides (CLIP). Recently, DM was shown to catalyze the release of CLIP from HLA-DR. We have investigated which peptides bound to HLA-DR are vulnerable to release upon encountering DM. By directed substitution of allele-specific anchor residues between CLIP and DR3-cognate peptides and the application of recombinant DM we show that DM catalyzes the release of those peptides bound to HLA-DR3 that do not have appropriate anchor residues and, hence, no optimal ligand binding motif. Thus, HLA-DM acts as a peptide editor, facilitating selection of peptides that stably bind to class II molecules for eventual presentation to the immune system from the pool of available peptides.

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A Novel Autoantibody against β2-Glycoprotein I/HLA Class II Complexes in Antiphospholipid Syndrome

10.5772/intechopen.97511 ◽

2021 ◽

Author(s):

Kenji Tanimura ◽

Yuki Sasagawa ◽

Masashi Deguchi ◽

Noriko Arase ◽

Hisashi Arase ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Clinical Manifestations ◽

Human Leukocyte ◽

Class Ii ◽

Cross Sectional Study ◽

Hla Class Ii ◽

Cross Sectional ◽

Leukocyte Antigen ◽

Glycoprotein I ◽

Hla Dr

We have found that a novel autoantibody against β2-glycoprotein I (β2GPI)/human leukocyte antigen (HLA) class II complexes (anti-β2GPI/HLA-DR) is involved in the pathogenesis of antiphospholipid syndrome (APS). It was also found that many APS patients who were negative for conventional antiphospholipid antibodies (aPLs) possessed anti-β2GPI/HLA-DR. These results suggested that anti-β2GPI/HLA-DR measurements may be more sensitive for diagnosing APS than conventional aPLs tests. Recurrent pregnancy loss (RPL) is one of the clinical manifestations of APS. Therefore, a prospective, multicenter, cross-sectional study were conducted to assess whether anti-β2GPI/HLA-DR is also associated with RPL. This study of 227 couples with RPL revealed that 22.9% (52/227) of RPL women tested positive for anti-β2GPI/HLA-DR, and 24 (19.8%) of the 121 couples with unexplained RPL tested positive for anti-β2GPI/HLA-DR. Interestingly, thirty-five of the 52 (67.3%) RPL patients who were positive for anti-β2GPI/HLA-DR possessed no conventional aPLs of criteria. This novel autoantibody against β2GPI/HLA class II complexes may be a major risk factor for RPL, and it may be a promising biomarker for diagnosing APS.

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Designing Peptide-Based HIV Vaccine for Chinese

BioMed Research International ◽

10.1155/2014/272950 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 5

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.

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

International Journal of Gynecological Cancer ◽

10.1111/j.1525-1438.2007.00938.x ◽

2007 ◽

Vol 17 (6) ◽

pp. 1314-1321 ◽

Cited By ~ 9

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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Myeloid phenotypes in severe COVID-19 predict secondary infection and mortality: a pilot study

Annals of Intensive Care ◽

10.1186/s13613-021-00896-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Clémence Marais ◽

Caroline Claude ◽

Nada Semaan ◽

Ramy Charbel ◽

Simon Barreault ◽

...

Keyword(s):

Critically Ill ◽

Host Response ◽

Secondary Infection ◽

Myeloid Cells ◽

Suppressor Cells ◽

Human Leukocyte ◽

Myeloid Derived Suppressor Cells ◽

Phenotypic Characteristics ◽

Leukocyte Antigen ◽

Hla Dr

Abstract Background De-regulated host response to severe coronavirus disease 2019 (COVID-19), directly referring to the concept of sepsis-associated immunological dysregulation, seems to be a strong signature of severe COVID-19. Myeloid cells phenotyping is well recognized to diagnose critical illness-induced immunodepression in sepsis and has not been well characterized in COVID-19. The aim of this study is to review phenotypic characteristics of myeloid cells and evaluate their relations with the occurrence of secondary infection and mortality in patients with COVID-19 admitted in an intensive care unit. Methods Retrospective analysis of the circulating myeloid cells phenotypes of adult COVID-19 critically ill patients. Phenotyping circulating immune cells was performed by flow cytometry daily for routine analysis and twice weekly for lymphocytes and monocytes subpopulations analysis, as well as monocyte human leukocyte antigen (mHLA)-DR expression. Results Out of the 29 critically ill adult patients with severe COVID-19 analyzed, 12 (41.4%) developed secondary infection and six patients died during their stay. Monocyte HLA-DR kinetics was significantly different between patients developing secondary infection and those without, respectively, at day 5–7 and 8–10 following admission. The monocytes myeloid-derived suppressor cells to total monocytes ratio was associated with 28- and 60-day mortality. Those myeloid characteristics suggest three phenotypes: hyperactivated monocyte/macrophage is significantly associated with mortality, whereas persistent immunodepression is associated with secondary infection occurrence compared to transient immunodepression. Conclusions Myeloid phenotypes of critically ill COVID-19 patients may be associated with development of secondary infection, 28- and 60-day mortality.

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Binding of Human Thyrotropin Receptor Peptides to a Graves’ Disease-Predisposing Human Leukocyte Antigen Class II Molecule

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.3.6376 ◽

2000 ◽

Vol 85 (3) ◽

pp. 1176-1179 ◽

Cited By ~ 1

Author(s):

Yoshikuni Sawai ◽

Leslie J. DeGroot

Keyword(s):

Human Leukocyte Antigen ◽

Human Leukocyte ◽

Class Ii ◽

Hla Class Ii ◽

Graves Disease ◽

T Cell Repertoire ◽

Thyrotropin Receptor ◽

Cell Repertoire ◽

Peptide Epitopes ◽

Leukocyte Antigen

Abstract Abstract There are many reports that Graves’ disease (GD) is associated with certain human leukocyte antigen (HLA) molecules, in particular DR3. Here we examined the characteristics of binding of human TSH receptor (TSHR) peptides to this disease-associated HLA class II molecule. DR3 molecules bind TSHR immuonodominant peptide epitopes with intermediate affinity. On the contrary, DR3 binds nonimmunogenic peptides either with poor affinity or not at all, with one exceptional peptide that has extremely high affinity. These results suggest that susceptibility to GD associated with inheritance of a specific HLA class II gene is due to the influence of the HLA molecule-TSHR peptide complex on the T cell repertoire.

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