Oral Presentation CD1-MR1 Workshop 2025

Dissecting the human postnatal development of unconventional T cells for their therapeutic potential (#23)

Louis Perriman 1 2 3 , Naeimeh Tavakolinia 1 2 4 , Marziyeh Taheri 1 2 4 , Kevin Wijanarko 2 4 5 , Sedigheh Jalali 1 2 , Christopher Mene 1 2 , Shou Li 1 2 , Peter F Hickey 6 7 , Daniela Amann-Zalcenstein 6 7 , William Wing Ho Ho 6 , Tracey M Baldwin 6 , Adam T Piers 8 9 , Igor E Konstantinov 2 8 10 , Jeremy Anderson 2 11 , Edouard G Stanley 2 5 , Paul V Licciardi 2 11 , George Kannourakis 3 12 , Shalin H Naik 7 13 , Hui-Fern Koay 14 , Laura K Mackay 14 , Adam P Uldrich 14 , Stuart P Berzins 12 14 , Daniel G Pellicci 1 2 8 14
  1. Cellular Immunology, Murdoch Royal Children's Hospital, Melbourne, VIC, Aus
  2. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
  3. Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia
  4. Division of Medicine, Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Aus
  5. Stem Cell Medicine, Murdoch Children's Research Institute, Parkville, VIC, Australia
  6. Genomics laboratory and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Aus
  7. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Aus
  8. Melbourne Centre for Cardiovacular Genomics and Regenerative Medicine, Melbourne, VIC, Australia
  9. Heart Research, Murdoch Children's Research Institute, Parkville, VIC, Australia
  10. Cardiothoracic Surgery, Royal Children's Hospital, Melbourne, VIC, Australia
  11. Vaccine Immunology, Murdoch Children's Research Institute, Melbourne, VIC, Australia
  12. School of Science Psychology and Sport, Federation University, Ballarat, VIC, Aus
  13. Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  14. Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia

Unconventional T cells are a subset of T cells that recognise a range of non-peptide antigens, such as lipids, vitamin B metabolites, and phosphoantigens. These antigens are presented by non-classical antigen-presenting molecules, including CD1, MHC-related 1 (MR1), and butyrophilin molecules. Unconventional T cells include CD1-restricted T cells such as natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells. Unconventional T cells can rapidly produce large amounts of cytokines upon activation and are suggested to be crucial in the interface of innate and adaptive immunity. These cells are implicated in various human diseases, including cancer and autoimmune disorders, with alterations in both their frequency and function noted. Therefore, understanding their developmental pathways is critical for uncovering potential mechanisms behind these diseases, and could inform the development of targeted therapies to modulate number and function of unconventional T cells for clinical benefit. Through a combination of high-dimensional flow cytometry and transcriptomic analysis, we revealed the distinct yet overlapping developmental pathways of unconventional T cells in the human postnatal thymus. Our findings include gene signatures suggesting that both MAIT and NKT cells require further extrathymic maturation to attain full functional capacity where as Vγ9Vδ2 T cells do not. These findings could inform the development of novel therapeutic strategies, including off-the-shelf approaches that harness the unique properties of unconventional T cells in diverse disease settings.