Dataset Information

Direct quantification of viral epitope abundance reveals the importance of direct and cross-presentation in driving CTL responses during influenza infection

ABSTRACT: The magnitude of CD8+ T lymphocyte (CTL) responses to infection is a function of the available naïve T cell repertoire, combined with the context and duration of antigen presentation. Whilst T cell repertoires are relatively easily studied, the context and abundance of epitopes presented on infected cells and dendritic cells (DCs) and their subsequent impact on CTL responses are generally poorly understood. Using quantitative mass spectrometry, we identified and quantified the abundance of 21 class 1 Major Histocompatibility Complex molecule (MHCI)-restricted influenza A virus (IAV)-derived peptides following either direct presentation or cross-presentation. All identified peptides, including seven novel epitopes, elicited T cell responses in infected C57BL/6 mice. Quantitation of IAV epitopes displayed via direct presentation showed a maintenance of relative epitope abundance across distinct cell types, reflecting common antigen processing mechanisms. Comparison of epitope levels displayed via direct presentation and cross-presentation revealed a broad range of directly presented epitope abundances, which was normalised during cross-presentation. Further, we observed a clear disparity in the abundance of the two key immunodominant IAV antigens, wherein direct infection drove optimal nucleoprotein (NP)366-374 presentation, while cross-presentation was optimal for acid polymerase (PA)224-233 presentation. This study provides a detailed dissection of viral pMHCI abundance after infection and reveals the importance of both direct and cross-presentation in driving dominant CTL responses. The study also demonstrates how empirical assessment of epitope abundance in both modes of antigen presentation is necessary to fully understand the immunogenicity and response magnitude to T cell epitopes.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Dendritic Cell, Cell Culture

DISEASE(S): Influenza

SUBMITTER: Nathan Croft

LAB HEAD: Anthony Purcell

PROVIDER: PXD012728 | Pride | 2019-07-02

REPOSITORIES: Pride

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Publications

Quantification of epitope abundance reveals the effect of direct and cross-presentation on influenza CTL responses.

Wu Ting T Guan Jing J Handel Andreas A Tscharke David C DC Sidney John J Sette Alessandro A Wakim Linda M LM Sng Xavier Y X XYX Thomas Paul G PG Croft Nathan P NP Purcell Anthony W AW La Gruta Nicole L NL

Nature communications 20190628 1

The magnitude of T cell responses to infection is a function of the naïve T cell repertoire combined with the context and duration of antigen presentation. Using mass spectrometry, we identify and quantify 21 class 1 MHC-restricted influenza A virus (IAV)-peptides following either direct or cross-presentation. All these peptides, including seven novel epitopes, elicit T cell responses in infected C57BL/6 mice. Directly presented IAV epitopes maintain their relative abundance across distinct cell ...[more]

PMID: 31253788

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Project description:This a model from the article: A dynamical perspective of CTL cross-priming and regulation: implications for cancer immunology. Wodarz D, Jansen VA. Immunol Lett 2003 May 1;86(3):213-27 12706524 , Abstract: Cytotoxic T lymphocytes (CTL) responses are required to fight many diseases such as viral infections and tumors. At the same time, they can cause disease when induced inappropriately. Which factors regulate CTL and decide whether they should remain silent or react is open to debate. The phenomenon called cross-priming has received attention in this respect. That is, CTL expansion occurs if antigen is recognized on the surface of professional antigen presenting cells (APCs). This is in contrast to direct presentation where antigen is seen on the surface of the target cells (e.g. infected cells or tumor cells). Here we introduce a mathematical model, which takes the phenomenon of cross-priming into account. We propose a new mechanism of regulation which is implicit in the dynamics of the CTL: According to the model, the ability of a CTL response to become established depends on the ratio of cross-presentation to direct presentation of the antigen. If this ratio is relatively high, CTL responses are likely to become established. If this ratio is relatively low, tolerance is the likely outcome. The behavior of the model includes a parameter region where the outcome depends on the initial conditions. We discuss our results with respect to the idea of self/non-self discrimination and the danger signal hypothesis. We apply the model to study the role of CTL in cancer initiation, cancer evolution/progression, and therapeutic vaccination against cancers. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Wodarz D, Jansen VA. (2003) - version=1.0 The original CellML model was created by: Catherine Lloyd c.lloyd@auckland.ac.nz The University of Auckland This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Sanjuan2013 - Evolution of HIV T-cell epitope, immune activation model Model of cellular immune response against HIV. This model is described in the article: Immune activation promotes evolutionary conservation of T-cell epitopes in HIV-1. Sanjuán R, Nebot MR, Peris JB, Alcamí J. PLoS Biol. 2013 Apr;11(4):e1001523 Abstract: The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4(+) helper T lymphocytes (TH cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when TH cell infection is concomitant to epitope recognition (trans-infection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved TH epitopes may be counterproductive. Note from the author: this version of the model is more general that the one described in the paper. This is because: (i) it can consider simultaneously Th-epitope escape mutants, CTL-epitope escape mutants and full T-cell (Th and CTL) escape mutants, by setting the mutation rate of Th and CTL escape mutants to zero. (ii) It allows for back mutations, which were ignored in all the simulations shown in the paper. (iii) It allows for a fitness cost of escape mutants, which was set to zero in the article. (iv) pAPCs can be infected and produce viruses (the rate of viral production for pAPCs was set to zero in the paper). This model is hosted on BioModels Database and identified by: MODEL1302180001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Direct quantification of viral epitope abundance reveals the importance of direct and cross-presentation in driving CTL responses during influenza infection

Publications

Quantification of epitope abundance reveals the effect of direct and cross-presentation on influenza CTL responses.

Similar Datasets

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