Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8+ Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β

Henrique Borges da Silva, Changwei Peng, Haiguang Wang, Kelsey M. Wanhainen, Chaoyu Ma, Sharon Lopez, Alexander Khoruts, Nu Zhang, Stephen C. Jameson

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Tissue-resident memory (Trm) CD8 + T cells mediate protective immunity in barrier tissues, but the cues promoting Trm cell generation are poorly understood. Sensing of extracellular adenosine triphosphate (eATP) by the purinergic receptor P2RX7 is needed for recirculating CD8 + T cell memory, but its role for Trm cells is unclear. Here we showed that P2RX7 supported Trm cell generation by enhancing CD8 + T cell sensing of TGF-β, which was necessary for tissue residency. P2RX7-deficient Trm cells progressively decayed in non-lymphoid tissues and expressed dysregulated Trm-specific markers. P2RX7 was required for efficient re-expression of the receptor TGF-βRII through calcineurin signaling. Forced Tgfbr2 expression rescued P2RX7-deficient Trm cell generation, and TGF-β sensitivity was dictated by P2RX7 agonists and antagonists. Forced Tgfbr2 also rescued P2RX7-deficient Trm cell mitochondrial function. Sustained P2RX7 signaling was required for long-term Trm cell maintenance, indicating that P2RX7 signaling drives induction and CD8 + T cell durability in barrier sites.

Original languageEnglish (US)
Pages (from-to)158-171.e6
JournalImmunity
Volume53
Issue number1
DOIs
StatePublished - Jul 14 2020

Bibliographical note

Funding Information:
We thank Wanjun Chen (NIDCR) for providing the MiT-Tgfbr2 overexpression vector. We also thank the members of the Jamequist lab for critically reviewing the manuscript. S.C.J. was funded by NIAID ( R01 AI038903 and AI145147 ). H.B.d.S. was funded by NIAID ( K99/R00 AI139381 ) and a Paul C. Shiverick/CRI Irvington fellowship.

Funding Information:
We thank Wanjun Chen (NIDCR) for providing the MiT-Tgfbr2 overexpression vector. We also thank the members of the Jamequist lab for critically reviewing the manuscript. S.C.J. was funded by NIAID (R01 AI038903 and AI145147). H.B.d.S. was funded by NIAID (K99/R00 AI139381) and a Paul C. Shiverick/CRI Irvington fellowship. H.B.d.S. and S.C.J. conceived the project. H.B.d.S. and S.C.J. conceived the experiments. A.K. N.Z. and S.C.J. provided mice and reagents for all experiments. H.B.d.S. C.P. H.W. K.M.W. C.M. and S.L. performed the experiments and analyzed the data. H.B.d.S. and S.C.J. wrote the manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • P2RX7
  • TGF-β
  • eATP
  • memory CD8 T cells
  • non-lymphoid tissue

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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