Immunological Consequences of Age-Related Changes in Proteostasis
T cells are crucially involved in the surveillance of tissues to eliminate infected or transformed cells. This function depends on the recognition of small peptide fragments presented by MHC molecules on the surface of cells. This universe of MHC presented peptides is termed the ligandome. The presentation of peptides resulting from pathogen-derived or mutated proteins triggers the activation of T cells, whereas peptides derived from self-proteins are important for the induction of T cell tolerance in the thymus. Peptides recognized by T cells are generated by different cellular proteases and protein degradation pathways such as the autophagic-lysosomal pathway (autophagy), which contribute to the establishment of a balanced and functional universe of cellular proteins, the proteome. During ageing, the proteostasis network becomes progressively burdened by increasing loads of misfolded proteins and proteins that have been damaged by oxidative stress, while both central protein degradation pathways, the ubiquitin-proteasome system and autophagy undergo alterations. As a consequence, the age-dependent decline in the ability of cells to maintain a functional proteome is regarded as a major driver of age-related cellular dysfunction and degenerative diseases.
This project aims to describe the influence of age-induced changes in proteostasis with regard to the peptides presented by MHC molecules and potential consequences of the recognition of these peptides by T cells. We will characterize the effects regarding both, peptides derived from a disturbed repertoire of self-proteins and in addition on peptides of viral origin.
The project will be divided into four different research sections:
- Characterization of the proteome/ligandome changes between young vs. old mice.
- Identification of the proteome/ligandome of senescent cells & cells with disturbed proteostasis.
- Characterization of immune responses directed against an aged ligandome.
- Characterization of the ligandome and immune responses of young and aged mice against LCMV and influenza virus.
Principle Investigators
Dr. Hansjörg Schild, Institute of Immunology, University Medical Center (person of contact email)
Dr. Stefan Tenzer, Institute for Immunology, University Medical center
Dr. Christian Behl, Institute of Pathobiochemistry, University Medical Center
Hans Christian Probst, Institute for Immunology, University Medical Center
Katja Luck, Institute of Molecular Biology, JGU
Dr. Matthias Gaida, TRON gGmbH
