Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling

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.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2024-10-09
DOI
https://doi.org/10.1084/jem.20240354
Citations
10
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
2.40

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article

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling

Aly Fayed, Alice Brandli, Joelyn Wong, Hui‐Fern Koay et al.
10 citations
The Journal of Experimental Medicine
Immune Cell Function and Interaction
2.40
article

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling

Aly Fayed, Alice Brandli, Joelyn Wong, Hui‐Fern Koay, Laura K. Mackay, Jeffrey Y. W. Mak, Calvin Xu, Xin Huang, David P. Fairlie, Rohit D’Costa, Claire L. Gordon, Lynette Beattie, Andreas Obers, Dale Ian Godfrey, Graham Starkey, Allison Clatch, Minyi Qin
article en
10 citations

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.

The Journal of Experimental MedicineVol. 221(12)
China Pharmaceutical University (CN), The University of Queensland (AU), The University of Melbourne (AU), Florey Institute of Neuroscience and Mental Health (AU), Discovery Institute (US), BirdLife Australia (AU), Eastern Health (AU), Peter Doherty Institute (AU), ARC Centre of Excellence for Innovations in Peptide and Protein Science (AU), Melbourne Health (AU), Austin Health (AU), Nanjing University (CN)
Sylvia and Charles Viertel Charitable Foundation, National Institutes of Health, Australian Research Council, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 11%
Immune Cell Function and Interaction
2.40
DOIOpen Access PDFOpenAlex
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