Deciphering the role of NIK in T cell central tolerance and autoimmunity

• Applicant: Dr. Claudia Haftmann
• Subject Area: Immunology
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 316994258

Central T cell tolerance occurs in the thymus, where developing thymocytes have to successfully master various checkpoints before they can enter the pool of mature peripheral T cells. In the thymus specialized medullary thymic epithelial cells (mTECs) present tissue specific (self)-antigens (TSAs) to developing T cells, eliminating those with a high-affinity TCR for self during negative selection. Additionally, in a stochastic manner, some of the autoreactive T cells are instructed to become regulatory T cells (Tregs), which leave the thymus to largely control peripheral tolerance. Both the maturation of mTECs as well as their ability to present TSAs depends on NF-kB-inducing kinase (NIK). Mice lacking functional NIK develop mild late-onset multi-organ autoimmunity and detectable levels of autoantibodies in the serum. However, it remained elusive how exactly NIK influences mTEC development and negative selection. Therefore, we generated a conditional NIKfl/fl mouse and crossed it to the thymic stroma specific Foxn1-Cre+ mouse, resulting in the TEC specific deletion of NIK. In contrast to germline deletion of NIK, TEC-specific deletion oft the NIK gene resulted in a fatal autoimmune phenotype manifesting shortly after birth. This phenotype is perhaps the most severe autoimmune pathology observed in mice to date. With this proposal we aim to understand the role of NIK in i) TEC maturation and consequently in ii) central tolerance. We will characterize the impact of the TEC specific NIK deletion on the developing T cell pool, including the formation and stability of Tregs. Further, we will address the question as to why TEC specific ablation of NIK results in a more severe autoimmune phenotype compared to germline deleted NIK, possibly unraveling yet unknown mechanisms of tolerance.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professor Dr. Burkhard Becher