The causes of MHC-I-opathies in cellular stress

• Applicant: Professor Dr. Sebastian Springer
• Subject Area: Cell Biology ; Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460154834

Major histocompatibility complex (MHC) class I molecules (termed human leukocyte antigen (HLA I in human) are essential for mounting a cytotoxic adaptive response to intracellular pathogens and tumors. The specificity of the adoptive response relies on the accurate and efficient presentation of peptide fragments from non-self (e.g., viral or neoplastic) proteins by one of each six potentially dif-ferent HLA I molecules from two equidominantly expressed alleles of HLA-A, HLA-B and HLA-C loci in each individual. Discrimination of self from non-self is safeguarded by the elimination of auto-reactive T cells. Nevertheless, a group of autoreactive diseases (e.g. ankylosing spondylitis and oth-er spondyloarthropathies, Behçet’s disease, psoriasis, birdshot chorioretinopathy) display a strong genetic link to individual HLA I alleles. Accumulation of vast genetic data over the last four decades has recently lead to classification of those autoreactive diseases as MHC-I-opathies. Interestingly, in diseased individuals, disease-related CD8+ T cell responses to specific peptide-HLA I complexes have not been detected. This suggests that there are additional immune mechanisms (e.g innate response from NK cells directed towards HLA-I; cellular stress), independent of the presented peptides. Our previous work on numerous HLA I molecules supports the idea that certain HLA I allo-types can be biochemically unstable, and that low protein stability can result in intracellular accumu-lation of misfolded HLA I proteins. In such cases, antigen presentation by HLA I is diminished at the cell surface, and accumulated HLA I can stimulate cellular stress pathways such as unfolded protein response (UPR). In this work, we will determine the stability of each individual HLA I protein associated with MHC-I-opathies, assess their link to cellular stress, and define common structural features among them. Finally, according to our expertise, we will perform screens with small molecules to improve their stability and prevent pathological phenotypes in cellular models.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Martin Zacharias