Forward genetic analysis of T regulatory cell development and function. (360G-Wellcome-090794_Z_09_A)

Regulatory T (TREG) cells maintain tolerance to self and control autoimmune deviation. They prevent runaway responses to pathogens and allergens and help maintain a balance with obligate microbial flora. They maintain allogeneic transplant tolerance in experimental models but also facilitate tumour escape from immune monitoring. It is because of this fundamental importance for immune function and their great potential for therapeutic modulation that TREG cells have attracted extraordinary interest. However, our understanding of their development remains incomplete. Using a forward genetic approach, N-ethyl-N-nitrosourea (ENU) germline mutagenesis, Philip Ashton-Rickardt's laboratory aim to identify all non-redundant genes required for the development of TREG cells. Given the time constraints of a 3-year fellowship, this project aims to identify 2 such genes. 1500 ENU mutant C57BL/6 mice will be subjected to a single-stage screen with the aim of identifying 2 mutants with abnormal TREG development. Transmissibility of the mutations will be confirmed and homozygous mutant strains established. Positional cloning and exon sequencing will identify the culpable mutation in the affected gene. In depth phenotypic analysis will determine how the affected gene controls the development and function of TREG cells and how they suppress allo-reactivity and autoimmunity in model systems.