Invited Speaker CD1-MR1 Workshop 2025

Understanding unconventional T cell development to generate an ‘off the shelf’ immunotherapy to treat human diseases (#59)

Daniel Pellicci 1 2 3 , Naeimeh Tavakolinia 1 3 , Kevin Wijanarko 2 3 , Louis Perriman 1 2 3 4 , Sedigheh Jalali 3 , Marziyeh Taheri 1 3 , Peter Hickey 5 , Daniela Amann-Zalcenstein 5 6 , Tracey Baldwin 5 , Stuart Berzins 1 4 7 , Adam Uldrich 1 , Edouard Stanley 2 3
  1. Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
  2. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
  3. Murdoch Children's Research Institute, Parkville, VIC, Australia
  4. The Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia
  5. Genomics Laboratory and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  6. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
  7. Federation University, Ballarat, VIC, Australia

Unconventional T cells represent more than 10% of total T cells within the blood and tissues of humans and play critical roles in cancer and infection. Human unconventional T cells exhibit dual effector functions; they rapidly secrete cytokines upon stimulation, and they express granzymes and perforin that enables them to lyse infected or cancerous cells. Our research has deciphered how unconventional T cell subsets including MAIT cells, gamma delta T cells and NKT cells develop in the human thymus. We reveal that all three subsets develop via a linear pathway defined by the upregulation of the transcription factor PLZF and the Killer cell lectin-like receptor subfamily B, member 1 (CD161). Further, functional programming of unconventional T cells takes place in the human thymus. We demonstrate that the development of unconventional T cells can be faithfully reproduced using artificial thymus organoids, which allows for detailed interrogation of this process by removal of key factors that influence their development. Furthermore, we demonstrate that our unconventional T cells can be developed as an “off the shelf’ immunotherapy. Collectively, our work reveals how understanding unconventional T cell development in the human thymus has led to new opportunities to utilise these cells to treat human diseases such as cancer or microbial resistant infections.