Flash Talk & Poster CD1-MR1 2024

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signalling (#128) (#63)

Calvin Xu 1 , Andreas Obers 1 , Minyi Qin 1 , Alice Brandli 2 , Joelyn Wong 3 , Xin Huang 3 , Lynette Beattie 1 , Laura K Mackay 1 , Dale I Godfrey 1 , Hui-Fern Koay 1
  1. Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VICTORIA, Australia
  2. Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia
  3. The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia

Unconventional T cells, including MAIT, γδT, and NKT cells, comprise T-bet+, IFN-γ-producing, and RORγt+, IL-17-producing subsets which play differing roles in disease. Despite these cells’ collective abundance in tissues like the liver, how their numbers and cytokine-producing subsets are regulated is poorly characterised.

Following tissue damage, release of ATP and nicotinamide adenine dinucleotide (NAD) by injured cells is detected by and activates the purinergic P2X7 receptor (P2RX7). P2RX7 activation on T cells can induce cell death, where NAD-induced cell death additionally requires the ADP-ribosyltransferase, ARTC2. We show that human peripheral blood MAIT, γδT, and NKT cells express P2RX7, where their mouse T-bet+ counterparts co-expressed ARTC2 and P2RX7, especially within liver. Intriguingly, we identify two ARTC2hiP2RX7+ non-MAIT/NKT αβT-cell subsets that, like MAIT/NKT cells, co-expressed the master transcription factors PLZF and T-bet. These T-bet+ unconventional T and PLZF+ αβT cells in thymus upregulated ARTC2 and P2RX7 following retinoic acid treatment. After exposure to tissue damage ex vivo, liver unconventional T cells underwent cell death in a manner rescued by ARTC2 or P2RX7 blockade. ARTC2/P2RX7 blockade consequently increased the numbers of IFN-γ+, and particularly, IFN-γ+IL-4+ T cells after stimulation ex vivo, revealing novel IFN-γ-IL-4 co-producing MAIT and αβT-cell subsets. Lastly, P2RX7 activation in vivo, via intravenous administration of NAD, rapidly and selectively depleted multiple liver T-bet+ unconventional T and PLZF+T-bet+ αβT-cell subsets, where this depletion was partially rescued by ARTC2 blockade.

This study overall suggests that P2RX7 activation plays an important role in controlling functionally-similar unconventional T-cell subsets, especially within liver. Inhibiting P2RX7 may boost unconventional T cell-mediated immune responses in the presence of tissue damage-associated metabolites, such as during infection and within tumours. These findings provide insight into mechanisms that govern unconventional T-cell frequencies and functional diversity, which may inform the use of these cells in future immunotherapies.