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Title: | Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling. | Austin Authors: | Xu, Calvin;Obers, Andreas;Qin, Minyi;Brandli, Alice;Wong, Joelyn;Huang, Xin;Clatch, Allison;Fayed, Aly;Starkey, Graham M ;D'Costa, Rohit;Gordon, Claire L ;Mak, Jeffrey Y W;Fairlie, David P;Beattie, Lynette;Mackay, Laura K;Godfrey, Dale I;Koay, Hui-Fern | Affiliation: | Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.;The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Australia. The Florey Institute of Neuroscience and Mental Health , Melbourne, Australia. Infectious Diseases Victorian Liver Transplant Unit Department of Surgery, The University of Melbourne, Austin Health, Melbourne, Australia. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.;Department of Infectious Diseases, Austin Health, Melbourne, Australia.;North Eastern Public Health Unit, Austin Health , Melbourne, Australia. ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland , Brisbane, Australia. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. |
Issue Date: | 2-Dec-2024 | Date: | 2024 | Publication information: | The Journal of Experimental Medicine 2024-12-02; 221(12) | Abstract: | Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T (γδT) cells, comprise distinct T-bet+, IFN-γ+ and RORγt+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, γδT, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death. Mouse peripheral T-bet+ MAIT1, γδT1, and NKT1 cells, especially in liver, co-express ARTC2 and P2RX7. These markers could be further upregulated upon exposure to retinoic acid. Blocking ARTC2 or inhibiting P2RX7 protected MAIT1, γδT1, and NKT1 cells from cell death, enhanced their survival in vivo, and increased the number of IFN-γ-secreting cells without affecting IL-17 production. Importantly, this revealed the existence of IFN-γ and IL-4 co-producing unconventional T-cell populations normally lost upon isolation due to ARTC2/P2RX7-induced death. Administering extracellular NAD in vivo activated this pathway, depleting P2RX7-sensitive unconventional T cells. Our study reveals ARTC2/P2RX7 as a common regulatory axis modulating the unconventional T-cell compartment, affecting the viability of IFN-γ- and IL-4-producing T cells, offering important insights to facilitate future studies into how these cells can be regulated in health and disease. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/35600 | DOI: | 10.1084/jem.20240354 | ORCID: | 0000-0003-0753-7639 0009-0005-8768-0153 0009-0005-9404-3662 0000-0002-4842-3438 0000-0001-7541-0715 0000-0002-7278-3070 0009-0007-5436-7608 0000-0001-6076-8140 0000-0002-4285-1343 0000-0003-2313-2623 0000-0001-5172-4728 0000-0002-8011-4539 0000-0002-7856-8566 0000-0002-5794-7233 0000-0002-8496-6632 0000-0002-3009-5472 0000-0002-3236-9609 |
Journal: | The Journal of Experimental Medicine | PubMed URL: | 39560665 | ISSN: | 1540-9538 | Type: | Journal Article | Subjects: | Receptors, Purinergic P2X7/metabolism Receptors, Purinergic P2X7/genetics Interferon-gamma/metabolism Interleukin-4/metabolism Mucosal-Associated Invariant T Cells/immunology Mucosal-Associated Invariant T Cells/metabolism Natural Killer T-Cells/immunology Natural Killer T-Cells/metabolism Receptors, Antigen, T-Cell, gamma-delta/metabolism |
Appears in Collections: | Journal articles |
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