Oral Presentation CD1-MR1 2024

NF-κB Transcription Factors in MAIT cell development (#54)

Tom Fulford 1 , Hui-Fern Koay 1 , Darryl Johnson 1 , Sebastian Scheer 2 , Hanno Nel 3 , Lorraine O'Reilly 4 , Steven Gerondakis 2 , Dale Godfrey 1
  1. Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
  2. Biomedicine Discovery Institute and Biochemistry and Molecular Biology, Monash University, Clayton, Vic, Australia
  3. Frazer Institute , The University of Queensland, Woolloongabba, Qld, Australia
  4. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

Mucosal Associated Invariant T (MAIT) represent a large proportion of antigen specific αβ T cells in both humans and mice and are a vital component of host defence against bacterial infection. However, the transcription factors that are important for MAIT cell development in the thymus remain poorly understood. Similar to other unconventional T cell subsets, MAIT cells exhibit a cell surface phenotype consistent with memory-like T cells. Given the important role of NF-kB proteins in the development and function of both unconventional T cells such as NKT cells, and memory T cells, we examined the impact of canonical and non-canonical NF-kB family members on mouse MAIT cell development using a gene knock-out approach. The impact of NF-kB-proteins on MAIT cell development was examined by flow cytometry in a number of NF-kB-deficient mouse strains. Strikingly, MAIT cell development was impaired in the thymus, spleen and liver of mice with a T cell deficiency in the transcription factor Rela (LckcreRelafl/fl) compared to LckcreRelawt/wt aged matched controls. This deficiency mostly affected T-bet+ MAIT cells compared to Rorγt+ MAIT cells, although IFNγ production is not impeded. MAIT cell development was also impaired in the thymus and spleen, but not liver, of Nfkb2-/- mice compared to Nfkb2+/- aged-matched controls. In contrast, we found no role for c-Rel in MAIT cell development. We identified a cell-intrinsic role for the transcription factor RelA in the development of MAIT cells, that disproportionately impacts the frequency of T-bet+ MAIT cells. We also identified an important role for the non-canonical NF-kB2 protein in thymic MAIT cell development, mirroring the effect of NF-kB-proteins on NKT cell development.