H2020Индивидуална стипендия2018–2020

MTBHLAE · Investigation of a novel immune cell type in Tuberculosis: characterization of the specificity, function and pathogen killing ability of T cells restricted by non-classical HLA-E molecules

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-07-01 → 2020-06-30
Финансиране от ЕС: 165 599 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Специфични протеини (пептиди) от бактерията, причиняваща туберкулоза, се изследват за способността им да активират защитни Т-клетки чрез молекулите HLA-E. Това помага за разработването на по-ефективни ваксини, тъй като тези молекули са почти еднакви при всички хора.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Investigation of a novel immune cell type in Tuberculosis: characterization of the specificity, function and pathogen killing ability of T cells restricted by non-classical HLA-E molecules

Tuberculosis remains the most deadly disease caused from a single infectious agent and the only vaccine available (BCG) gives incomplete and variable protection around the world. During this project we had the aim to identify novel Mycobacterium tuberculosis (Mtb)-derived peptides that could be presented by the antigen presenting molecules HLA-E for activation of protective T cells. These peptides have the potential to be used in the context of vaccine design to target these protective immune cells. HLA-E is an interesting molecule for vaccine design because, contrary to other antigen presenting molecules, it is highly conserved across humans. There are only two variants of this molecule expressed in humans, HLA-E*01:01 and HLA-E*01:03, with one single difference between the two which is outside of the peptide binding region. Regardless of this high similarity between the two molecules, some differences have been observed in peptide binding to the two molecules. Therefore we investigated differences and similarities in peptide binding to each molecule in order to select those peptides that are more relevant to both. In addition, we investigated what are the molecular characteristics necessary for HLA-E-peptide complexes to be recognized by T cell receptors (TCR), the receptor on the surface of immune cells that in necessary to activate them for a effective immune response. Ultimately, we test for the capacity of these peptides to induce the activation of protective T cells and to control the growth of Mtb bacteria. Our overall objectives are the following: - Identify a panel of Mtb peptides recognized via HLA-E. - Investigate differences in peptide binding to HLA-E*01:01 and HLA-E*01:03, as well as peptide presentation by these two molecules and T cell recognition, with the objective of selecting peptides presented by both alleles. - Determine the molecular pre-requisites for HLA-E-peptide-TCR interactions. - Test capacity of these peptides to induce CD8+ T cell activation and Mtb killing.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

ACADEMISCH ZIEKENHUIS LEIDEN · LeidenКоординаторНидерландия