A promiscuous T cell epitope-based HIV vaccine providing redundant population coverage of the HLA class II elicits broad, polyfunctional T cell responses in nonhuman primates

Studies in vitro have suggested that a species barrier exists in functional interaction between human histocompatibility leukocyte antigen (HLA) class II and mouse CD4 molecules. However, whether mouse CD4+ T cells restricted by HLA class II molecules are generated in HLA class II transgenic mice and respond to peptide antigens across this barrier has remained unclear. In an analysis of T cell responses to synthetic peptides in mice transgenic for HLA-DR51 and -DQ6, we found that DR51 and DQ6 transgenic mice acquired significant T cell response to influenza hemagglutinin-derived peptide 307-319 (HA 307) and Streptococcus pyogenes M12 protein-derived peptide 347-397 (M6C2), respectively. Inhibition studies with several monoclonal antibodies showed that transgenic HLA class II molecules presented these peptides to mouse CD4+ T cells. Furthermore, T cell lines specific for HA 307 or M6C2 obtained from the transgenic mice could respond to the peptide in the context of relevant HLA class II molecules expressed on mouse L cell transfectants that lack the expression of mouse MHC class II. These findings indicate that interaction between HLA class II and mouse CD4 molecules is sufficient for provoking peptide-specific HLA class II-restricted T cell responses in HLA class II transgenic mice.

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Induction of Polyomavirus-Specific CD8+T Lymphocytes by Distinct Dendritic Cell Subpopulations

Journal of Virology ◽

10.1128/jvi.75.1.544-547.2001 ◽

2001 ◽

Vol 75 (1) ◽

pp. 544-547 ◽

Cited By ~ 9

Author(s):

Donald R. Drake ◽

Mandy L. Shawver ◽

Annette Hadley ◽

Eric Butz ◽

Charles Maliszewski ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cell Epitope ◽

T Cell Responses ◽

T Cell Epitope ◽

Cell Responses ◽

Cd8 T Lymphocytes ◽

Cell Subpopulations ◽

Antigen Presenting

ABSTRACT Dendritic cells are pivotal antigen-presenting cells for generating adaptive T-cell responses. Here, we show that dendritic cells belonging to either the myeloid-related or lymphoid-related subset are permissive for infection by mouse polyomavirus and, when loaded with a peptide corresponding to the immunodominant anti-polyomavirus CD8+T-cell epitope or infected by polyomavirus, are each capable of driving expansion of primary polyomavirus-specific CD8+ T-cell responses in vivo.

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PREDIVAC: CD4+ T-cell epitope prediction for vaccine design that covers 95% of HLA class II DR protein diversity

BMC Bioinformatics ◽

10.1186/1471-2105-14-52 ◽

2013 ◽

Vol 14 (1) ◽

Cited By ~ 28

Author(s):

Patricio Oyarzún ◽

Jonathan J Ellis ◽

Mikael Bodén ◽

Boštjan Kobe

Keyword(s):

T Cell ◽

Cell Epitope ◽

Epitope Prediction ◽

Vaccine Design ◽

Class Ii ◽

Hla Class Ii ◽

Cd4 T Cell ◽

T Cell Epitope ◽

Protein Diversity ◽

T Cell Epitope Prediction

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A Truncated Alternative Spliced Isoform of Human Desmoglein 1 Contains a Specific T Cell Epitope Binding to the Pemphigus Foliaceus-Associated HLA Class II DRβ1*0102 Molecule

The Journal of Immunology ◽

10.4049/jimmunol.177.9.6517 ◽

2006 ◽

Vol 177 (9) ◽

pp. 6517-6526 ◽

Cited By ~ 13

Author(s):

Hugo Mouquet ◽

Sandrine Farci ◽

Pascal Joly ◽

Bernard Maillère ◽

Jonathan Leblond ◽

...

Keyword(s):

T Cell ◽

Cell Epitope ◽

Class Ii ◽

Hla Class Ii ◽

Pemphigus Foliaceus ◽

T Cell Epitope ◽

Epitope Binding

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An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope Is Functional in the Context of HLA-Restricted T Cell Responses

Arthritis & Rheumatology ◽

10.1002/art.39444 ◽

2016 ◽

Vol 68 (3) ◽

pp. 639-647 ◽

Cited By ~ 13

Author(s):

Charlotte de Wolf ◽

Ruurd van der Zee ◽

Ineke den Braber ◽

Tibor Glant ◽

Bernard Maillère ◽

...

Keyword(s):

T Cell ◽

Treg Cell ◽

Cell Epitope ◽

T Cell Responses ◽

Cd4 T Cell ◽

T Cell Epitope ◽

Cell Responses

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A systematic, unbiased mapping of CD8+ and CD4+ T cell epitopes in Yellow Fever vaccinees

10.1101/2020.03.28.012468 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anette Stryhn ◽

Michael Kongsgaard ◽

Michael Rasmussen ◽

Mikkel Nors Harndahl ◽

Thomas Østerbye ◽

...

Keyword(s):

T Cell ◽

Yellow Fever ◽

Cell Epitope ◽

T Cell Responses ◽

Hla Class I ◽

Class I ◽

T Cell Epitope ◽

T Cell Epitopes ◽

Cell Responses ◽

Epitope Discovery

1.AbstractExamining CD8+ and CD4+ T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8+ and 50 CD4+ T cell epitopes, many inducing strong and prevalent (i.e. immunodominant) T cell responses. Restricted by 40 and 14 HLA-class I and II allotypes, respectively, these responses have wide population coverage and might be of considerable academic, diagnostic and therapeutic interest. The broad coverage of epitopes and HLA overcame the otherwise confounding effects of HLA diversity and non-HLA background providing the first evidence of T cell immunodomination in humans. Also, double-staining of CD4+ T cells with tetramers representing the same HLA-binding core, albeit with different flanking regions, demonstrated an extensive diversification of the specificities of many CD4+ T cell responses. We suggest that this could reduce the risk of pathogen escape, and that multi-tetramer staining is required to reveal the true magnitude and diversity of CD4+ T cell responses. Our T cell epitope discovery approach uses a combination of 1) overlapping peptides representing the entire Yellow Fever virus proteome to search for peptides containing CD4+ and/or CD8+ T cell epitopes, 2) predictors of peptide-HLA binding to suggest epitopes and their restricting HLA allotypes, 3) generation of peptide-HLA tetramers to identify T cell epitopes, and 4) analysis of ex vivo T cell responses to validate the same. This approach is systematic, exhaustive, and can be done in any individual of any HLA haplotype. It is all-inclusive in the sense that it includes all protein antigens and peptide epitopes, and encompasses both CD4+ and CD8+ T cell epitopes. It is efficient and, importantly, reduces the false discovery rate. The unbiased nature of the T cell epitope discovery approach presented here should support the refinement of future peptide-HLA class I and II predictors and tetramer technologies, which eventually should cover all HLA class I and II isotypes. We believe that future investigations of emerging pathogens (e.g. SARS-CoV-2) should include population-wide T cell epitope discovery using blood samples from patients, convalescents and/or long-term survivors, who might all hold important information on T cell epitopes and responses.

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Identification of Novel HLA Class II-Restricted Neoantigens Derived from Driver Mutations

Cancers ◽

10.3390/cancers11020266 ◽

2019 ◽

Vol 11 (2) ◽

pp. 266 ◽

Cited By ~ 5

Author(s):

Susumu Iiizumi ◽

Junya Ohtake ◽

Naoko Murakami ◽

Taku Kouro ◽

Mamoru Kawahara ◽

...

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

Mononuclear Cells ◽

T Cell Responses ◽

Class Ii ◽

Hla Class Ii ◽

Cd4 T Cell ◽

Driver Mutations ◽

Cell Responses ◽

Kit D816v

Neoantigens derived from tumor-specific genetic mutations might be suitable targets for cancer immunotherapy because of their high immunogenicity. In the current study, we evaluated the immunogenicity of 10 driver mutations that are frequently expressed in various cancers using peripheral blood mononuclear cells from healthy donors (n = 25). Of the 10 synthetic peptides (27-mer) derived from these mutations, the six peptides from KRAS-G12D, KRAS-G12R, KRAS-G13D, NRAS-Q61R, PIK3CA-H1047R, and C-Kit-D816V induced T cell responses, suggesting that frequent driver mutations are not always less immunogenic. In particular, immune responses to PIK3CA-H1047R, C-Kit-D816V, KRAS-G13D, and NRAS-Q61R were observed in more than 10% of the donors. All six peptides induced human leukocyte antigen (HLA) class II-restricted CD4+ T cell responses; notably, PIK3CA-H1047R contained at least two different CD4+ T cell epitopes restricted to different HLA class II alleles. In addition, PIK3CA-H1047R and C-Kit-D816V induced antigen-specific CD8+ T cells as well, indicating that they might contain both HLA class I- and class II-restricted epitopes. Since the identified neoantigens might be shared by patients with various types of cancers and are not easily lost due to immune escape, they have the potential to be promising off-the-shelf cancer immunotherapy targets in patients with the corresponding mutations.

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Wilms Tumor Protein-1-Derived 9-Mer Peptide Induces CD4 T-Cell Responses in an HLA-DR Restricted Manner

Blood ◽

10.1182/blood.v120.21.4351.4351 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4351-4351

Author(s):

Shigeo Fuji ◽

Julia Fischer ◽

Markus Kapp ◽

Thomas G Bumm ◽

Hermann Einsele ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Responses ◽

Class Ii ◽

Hla Class Ii ◽

Cd4 T Cell ◽

Cell Responses ◽

Hla Dr ◽

Ifn Γ

Abstract Abstract 4351 Wilms‘ tumor protein-1 (WT1) is one of the most investigated tumor-associated antigens (TAA) in hematological malignancies. CD8 T-cell responses against several WT1-derived peptides have been characterized and are known to contribute to disease control after allogeneic hematopoietic stem cell transplantation (HSCT). Also the identification of human leukocyte antigen (HLA) class II-restricted CD4 T-cell epitopes from WT1 is a challenging task of T-cell-based cancer immunotherapy to improve the effectiveness of WT1 peptide vaccination. We found a highly immunogenic WT1 peptide composed of only 9 amino acids having the ability to induce IFN-γ secretion in CD4 T-cells in an HLA DR-restricted manner. This finding is of great interest as it was generally accepted that HLA class II binding peptides are composed of at least 12 amino acids being recognized by CD4 T-cells, whereas HLA class I binding peptides are composed of 8–11 amino acids being recognized by CD8 T-cells (Wang et al Mol. Immunol. 2002). However, both HLA class I and class II molecules bind to primary and secondary peptide anchor motifs covering the central 9–10 amino acids. Thus, considering this common structural basis for peptide binding there is a possibility that the WT1 9-mer peptide binds to HLA class II molecules, and induces CD4 T-cell responses. IFN-γ induction in response to several WT1 9-mer peptides was screened in 24 HLA-A*02:01 positive patients with acute myeloid leukemia or myelodysplastic syndrome after allogeneic HSCT. Responses to one WT1 9-mer peptide were exclusively detected in CD3+CD4+ T-cells of 2 patients after allogeneic HSCT, but not in CD3+CD4+ T-cells of their corresponding HSC donors. CD4+ T-cell responses to this WT1 9-mer peptide exhibited high levels of functional avidity, as IFN-γ induction was detected after stimulation with 100 ng peptide per mL. Peptide-induced IFN-γ production was confirmed with IFN-γ ELISPOT assays and the HLA restriction of the T-cell response was determined by HLA blocking antibodies. The reaction was significantly blocked by anti-pan HLA class II antibody (85 % reduction), but neither by pan-HLA class I nor by anti-HLA A2 antibody. To identify the subtype of HLA class II molecule, blocking assays with antibodies against HLA-DP, HLA-DR and HLA-DQ were performed. IFN-γ induction was completely abrogated by anti-HLA-DR antibody (99 % reduction) (fig 1, p value of unpaired student‘s t-test <0.0001 for the medium control vs anti-pan HLA class II antibody or anti-HLA-DR antibody, respectively). To test whether IFN-γ was exclusively induced in CD4 T cells, CD4 or CD8 T-cells were depleted from PBMC. Whereas CD8 T-cell depletion did not affect IFN-γ induction, CD4 T-cell depletion completely abrogated the WT1 9-mer peptide induced response (fig 2). CD4 T-cells responding to the WT1 9-mer peptide were indicated to be functional cytotoxic T-cells with an effector CD4 T-cell phenotype. Longitudinal analyses demonstrated the persistence and functionality of WT1 9-mer specific CD4 T-cells in PBMC of patients even at day 1368 after allogeneic HSCT. These data indicate for the first time that a TAA-derived 9-mer peptide can induce HLA class II-restricted CD4 T-cell responses. Vaccination with the characterized WT1 9-mer peptide can enhance the induction and maintenance of not only CD4 but also indirect CD8 T-cell responses. Considering that CD4 T-cells play an important role in tumor rejection, the possibility that other TAA-derived 9-mer peptides having the potential to induce CD4 T-cell responses should be explored in other settings of tumor immunology as well to improve vaccination strategies. Disclosures: No relevant conflicts of interest to declare.

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