Predicting MHC I restricted T cell epitopes in mice with NAP-CNB, a novel online tool.
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ABSTRACT:
SUBMITTER: Wert-Carvajal C
PROVIDER: S-EPMC8144223 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Predicting MHC I restricted T cell epitopes in mice with NAP-CNB, a novel online tool.
Wert-Carvajal Carlos C Sánchez-García Rubén R Macías José R JR Sanz-Pamplona Rebeca R Pérez Almudena Méndez AM Alemany Ramon R Veiga Esteban E Sorzano Carlos Óscar S CÓS Muñoz-Barrutia Arrate A
Scientific reports 20210524 1
Lack of a dedicated integrated pipeline for neoantigen discovery in mice hinders cancer immunotherapy research. Novel sequential approaches through recurrent neural networks can improve the accuracy of T-cell epitope binding affinity predictions in mice, and a simplified variant selection process can reduce operational requirements. We have developed a web server tool (NAP-CNB) for a full and automatic pipeline based on recurrent neural networks, to predict putative neoantigens from tumoral RNA ...[more]
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Project description:BackgroundPlasmodium falciparum circumsporozoite protein (CSP) is a leading malaria vaccine candidate antigen, known to elicit protective antibody responses in humans (RTS,S vaccine). Recently, a DNA prime / adenovirus (Ad) vector boost vaccine encoding CSP and a second P. falciparum antigen, apical membrane antigen-1, also elicited sterile protection, but in this case associated with interferon gamma ELISpot and CD8+ T cell but not antibody responses. The finding that CSP delivered by an appropriate vaccine platform likely elicits protective cell-mediated immunity provided a rationale for identifying class I-restricted epitopes within this leading vaccine candidate antigen.MethodsLimited samples of peripheral blood mononuclear cells from clinical trials of the Ad vaccine were used to identify CD8+ T cell epitopes within pools of overlapping 15mer peptides spanning portions of CSP that stimulated recall responses. Computerized algorithms (NetMHC) predicted 17 minimal class I-restricted 9-10mer epitopes within fifteen 15mers positive in ELISpot assay using PBMC from 10 HLA-matched study subjects. Four additional epitopes were subsequently predicted using NetMHC, matched to other study subjects without initial 15mer ELISpot screening. Nine of the putative epitopes were synthesized and tested by ELISpot assay, and six of these nine were further tested for CD8+ T cell responses by ELISpot CD4+ and CD8+ T cell-depletion and flow cytometry assays for evidence of CD8+ T cell dependence.ResultsEach of the nine putative epitopes, all sequence-conserved, recalled responses from HLA-matched CSP-immunized research subjects. Four shorter sequences contained within these sequences were identified using NetMHC predictions and may have contributed to recall responses. Five (9-10mer) epitopes were confirmed to be targets of CD8+ T cell responses using ELISpot depletion and ICS assays. Two 9mers among these nine epitopes were each restricted by two HLA supertypes (A01/B07; A01A24/A24) and one 9mer was restricted by three HLA supertypes (A01A24/A24/B27) indicating that some CSP class I-restricted epitopes, like DR epitopes, may be HLA-promiscuous.ConclusionsThis study identified nine and confirmed five novel class I epitopes restricted by six HLA supertypes, suggesting that an adenovirus-vectored CSP vaccine would be immunogenic and potentially protective in genetically diverse populations.
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