Objective Based on recent work from the Tuberculosis Research group in the Department of Infectious Diseases at LUMC on the discovery of highly in vivo expressed Mycobacterium tuberculosis (Mtb) antigens, using genome wide bioinformatics and immunomics approaches, I here propose to identify Mtb derived epitopes presented by HLA-E from the most immunogenic and protective antigens identified thus far during Mtb infection. HLA-E restricted Mtb specific CD8+ T-cells represent a novel human T-cell subset, which has only very recently been identified, and which could be highly relevant during the immune response to Mtb infection. HLA-E expression is enriched in Mtb phagosomes compared to classical HLA class Ia family members, thus facilitating HLA-E loading by Mtb peptides in infected cells (Grotzke et al. 2009). In contrast to most other HLA class I molecules, HLA-E is relatively resistant to down-regulation by HIV, a co-infection that is responsible for most of the TB related mortality [2]. Identification of novel epitopes will be performed in close collaboration with Dr. Thomas Abeel at TU Delft during a 3-month secondment where I will implement an improved prediction algorithm for the selection of the best candidate epitopes. I will subsequently determine the ability of the identified epitopes to induce superior CD8 T cell activation, including their ability to induce Mtb killing in infected human macrophages. I will further dissect the molecular determinants that control Mtb peptide binding to and presentation by the two HLA-E alleles in relation to T cell activation. Furthermore, I will look at specific molecular elements of the T cell receptor (TCR) associated with efficient T cell responses by TCR sequencing. Taken together, I will identify new Mtb HLA-E presented epitopes, dissect their binding to both alleles, determine their superior ability to induce T cells that are capable of Mtb killing and the resulting knowledge will be harnessed for TB vaccine development. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesmedical and health sciencesbasic medicineimmunologymedical and health scienceshealth sciencesinfectious diseasesRNA virusesHIVmedical and health sciencesclinical medicinepneumologytuberculosismedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2017 - Individual Fellowships Call for proposal H2020-MSCA-IF-2017 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator ACADEMISCH ZIEKENHUIS LEIDEN Net EU contribution € 165 598,80 Address Albinusdreef 2 2333 ZA Leiden Netherlands See on map Region West-Nederland Zuid-Holland Agglomeratie Leiden en Bollenstreek Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
