ESF-GS ABINEP / Teilprojekt M3.P6
Human mucosal-associated invariant T (MAIT) cells in age-associated Clostridioides difficile infections
Clostridioides difficile infection (CDI) causes severe and recurrent colitis with a high mortality rate. CDI is the nosocomial infection with highest medical and economical relevance in Germany, with increasing incidence. Beside long-term hospital stays, treatment of other bacterial infections with systemic antibiotics or the administration of immune suppressive drugs are important risk factors. Notably, especially patients older than 65 years are predisposed to suffer from CDI, suggesting age and immunosenescence to play a key role in the individual susceptibility to develop CDI.
Recent studies investigated the immune response in mouse models at the site of infection (intestinal mucosa), however, we do not know which immune cells mediate protection against CDI in the first place. It was observed that mice deficient for innate lymphoid cells succumb to CDI before the adaptive immune response is triggered. This suggests that especially the cells of the innate immune system protect against CDI. In humans, it was recently discovered that an innate-like T cell subset with anti-bacterial properties is highly abundant at the intestinal mucosa (2-10% of total T cells in the lamina propria). These mucosal-associated invariant T (MAIT) cells express high levels of C-type lectin CD161 and a semi-invariant T cell receptor (TCR) α-chain, Vα7.2, which enable them to sense ligands derived from bacterial riboflavin (vitamin B2) precursor 5-amino-6-d-ribitylaminouracil (5-A-RU) presented by antigen presenting cells. MAIT cells also show high expression of receptors for IL-12 and IL-18, thereby making them also sensitive for cytokine-mediated activation. Once activated, MAIT cells immediately secrete cytolytic effector molecules like perforin and granzymes but also immune modulating Th1 and Th17 cytokines like IFNγ and IL-17. With respect to C. difficile, we could already show that C. diffcile can directly activate MAIT cells in an antigen- and cytokine-dependent manner.
The aim of this project is to achieve a better understanding of T cell-mediated immunity in CDI in the context of immunosenescence. In particular, this project will focus on mucosal-associated invariant T (MAIT) cells, which constitute the most abundant anti-bacterial T cell subset. Central aims of this project are (i) the basic characterization of the interaction between MAIT cells and C. difficile, (ii) the investigation of the influence of aging on MAIT cell activity and (iii) the assessment of the MAIT cell phenotype in elderly patients suffering from C. difficile infection, as well as their protective effects.
PD Dr. Matthias Lochner, TWINCORE (https://www.twincore.de/de/forschungsgruppen/infektionsimmunologie/ag-mukosale-infektionsimmunologie)
Dr. Esteban Hernandez-Vargas, Frankfurt Institute for Advanced Studies (http://www.systemsmedicine.de)
PD Dr. med. Alexander Link, University Hospital at the OVGU Magdeburg (http://www.kghi.ovgu.de/)