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

doi:10.1016/j.immuni.2020.06.010

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 journal › Article › peer-review

90 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 language	English (US)
Pages (from-to)	158-171.e6
Journal	Immunity
Volume	53
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2020.06.010
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2020.06.010

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

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. ",

keywords = "P2RX7, TGF-β, eATP, memory CD8 T cells, non-lymphoid tissue",

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

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: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

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doi = "10.1016/j.immuni.2020.06.010",

language = "English (US)",

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T1 - Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8+ Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β

AU - Borges da Silva, Henrique

AU - Peng, Changwei

AU - Wang, Haiguang

AU - Wanhainen, Kelsey M.

AU - Ma, Chaoyu

AU - Lopez, Sharon

AU - Khoruts, Alexander

AU - Zhang, Nu

AU - Jameson, Stephen C.

N1 - 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.

PY - 2020/7/14

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N2 - 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.

AB - 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.

KW - P2RX7

KW - TGF-β

KW - eATP

KW - memory CD8 T cells

KW - non-lymphoid tissue

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