The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8+ T Cells

Trupti Vardam-Kaur; Sarah van Dijk; Changwei Peng; Kelsey M. Wanhainen; Stephen C. Jameson; Henrique Borges da Silva

doi:10.4049/jimmunol.2100555

The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8⁺ T Cells

Trupti Vardam-Kaur, Sarah van Dijk, Changwei Peng, Kelsey M. Wanhainen, Stephen C. Jameson, Henrique Borges da Silva

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Development of CD8⁺ central memory T (Tcm) and resident memory T (Trm) cells, which promote immunity in the circulation and in barrier tissues, respectively, is not completely understood. Tcm and Trm cells may arise from common precursors; however, their fate-inducing signals are elusive. We found that virus-specific effector CD8⁺ T cells display heterogeneous expression of the extracellular ATP sensor P2RX7. P2RX7-high expression is confined, at peak effector phase, to CD62L⁺ memory precursors, which preferentially form Tcm cells. Among early effector CD8⁺ T cells, asymmetrical P2RX7 distribution correlated with distinct transcriptional signatures, with P2RX7-high cells enriched for memory and tissue residency sets. P2RX7-high early effectors preferentially form both Tcm and Trm cells. Defective Tcm and Trm cell formation in P2RX7 deficiency is significantly reverted when the transcriptional repressor Zeb2 is ablated. Mechanistically, P2RX7 negatively regulates Zeb2 expression, at least partially through TGF-b sensing in early effector CD8⁺ T cells. Our study indicates that unequal P2RX7 upregulation in effector CD8⁺ T cells is a foundational element of the early Tcm/Trm fate. The Journal of Immunology, 2022, 208: 1686-1699.

Original language	English (US)
Pages (from-to)	1686-1699
Number of pages	14
Journal	Journal of Immunology
Volume	208
Issue number	7
DOIs	https://doi.org/10.4049/jimmunol.2100555
State	Published - Apr 1 2022

Bibliographical note

Funding Information:
This work was supported by National Institute of Allergy and Infectious Diseases grants awarded to H.B.d.S. (R00 AI139381) and to S.C.J. (R01 AI038903, AI145147).

Publisher Copyright:
Copyright © 2022 by The American Association of Immunologists, Inc. 0022-1767/22/$37.50

Keywords

Animals
CD8-Positive T-Lymphocytes
Immunologic Memory
Mice
Mice, Inbred C57BL
Receptors, Purinergic P2X7/genetics
Transforming Growth Factor beta/metabolism

PubMed: MeSH publication types

Journal Article

UN SDGs

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

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10.4049/jimmunol.2100555

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title = "The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8+ T Cells",

abstract = "Development of CD8+ central memory T (Tcm) and resident memory T (Trm) cells, which promote immunity in the circulation and in barrier tissues, respectively, is not completely understood. Tcm and Trm cells may arise from common precursors; however, their fate-inducing signals are elusive. We found that virus-specific effector CD8+ T cells display heterogeneous expression of the extracellular ATP sensor P2RX7. P2RX7-high expression is confined, at peak effector phase, to CD62L+ memory precursors, which preferentially form Tcm cells. Among early effector CD8+ T cells, asymmetrical P2RX7 distribution correlated with distinct transcriptional signatures, with P2RX7-high cells enriched for memory and tissue residency sets. P2RX7-high early effectors preferentially form both Tcm and Trm cells. Defective Tcm and Trm cell formation in P2RX7 deficiency is significantly reverted when the transcriptional repressor Zeb2 is ablated. Mechanistically, P2RX7 negatively regulates Zeb2 expression, at least partially through TGF-b sensing in early effector CD8+ T cells. Our study indicates that unequal P2RX7 upregulation in effector CD8+ T cells is a foundational element of the early Tcm/Trm fate. The Journal of Immunology, 2022, 208: 1686-1699.",

keywords = "Animals, CD8-Positive T-Lymphocytes, Immunologic Memory, Mice, Mice, Inbred C57BL, Receptors, Purinergic P2X7/genetics, Transforming Growth Factor beta/metabolism",

author = "Trupti Vardam-Kaur and {van Dijk}, Sarah and Changwei Peng and Wanhainen, {Kelsey M.} and Jameson, {Stephen C.} and {Borges da Silva}, Henrique",

note = "Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases grants awarded to H.B.d.S. (R00 AI139381) and to S.C.J. (R01 AI038903, AI145147). Publisher Copyright: Copyright {\textcopyright} 2022 by The American Association of Immunologists, Inc. 0022-1767/22/$37.50",

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doi = "10.4049/jimmunol.2100555",

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T1 - The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8+ T Cells

AU - Vardam-Kaur, Trupti

AU - van Dijk, Sarah

AU - Peng, Changwei

AU - Wanhainen, Kelsey M.

AU - Jameson, Stephen C.

AU - Borges da Silva, Henrique

N1 - Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases grants awarded to H.B.d.S. (R00 AI139381) and to S.C.J. (R01 AI038903, AI145147). Publisher Copyright: Copyright © 2022 by The American Association of Immunologists, Inc. 0022-1767/22/$37.50

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Development of CD8+ central memory T (Tcm) and resident memory T (Trm) cells, which promote immunity in the circulation and in barrier tissues, respectively, is not completely understood. Tcm and Trm cells may arise from common precursors; however, their fate-inducing signals are elusive. We found that virus-specific effector CD8+ T cells display heterogeneous expression of the extracellular ATP sensor P2RX7. P2RX7-high expression is confined, at peak effector phase, to CD62L+ memory precursors, which preferentially form Tcm cells. Among early effector CD8+ T cells, asymmetrical P2RX7 distribution correlated with distinct transcriptional signatures, with P2RX7-high cells enriched for memory and tissue residency sets. P2RX7-high early effectors preferentially form both Tcm and Trm cells. Defective Tcm and Trm cell formation in P2RX7 deficiency is significantly reverted when the transcriptional repressor Zeb2 is ablated. Mechanistically, P2RX7 negatively regulates Zeb2 expression, at least partially through TGF-b sensing in early effector CD8+ T cells. Our study indicates that unequal P2RX7 upregulation in effector CD8+ T cells is a foundational element of the early Tcm/Trm fate. The Journal of Immunology, 2022, 208: 1686-1699.

AB - Development of CD8+ central memory T (Tcm) and resident memory T (Trm) cells, which promote immunity in the circulation and in barrier tissues, respectively, is not completely understood. Tcm and Trm cells may arise from common precursors; however, their fate-inducing signals are elusive. We found that virus-specific effector CD8+ T cells display heterogeneous expression of the extracellular ATP sensor P2RX7. P2RX7-high expression is confined, at peak effector phase, to CD62L+ memory precursors, which preferentially form Tcm cells. Among early effector CD8+ T cells, asymmetrical P2RX7 distribution correlated with distinct transcriptional signatures, with P2RX7-high cells enriched for memory and tissue residency sets. P2RX7-high early effectors preferentially form both Tcm and Trm cells. Defective Tcm and Trm cell formation in P2RX7 deficiency is significantly reverted when the transcriptional repressor Zeb2 is ablated. Mechanistically, P2RX7 negatively regulates Zeb2 expression, at least partially through TGF-b sensing in early effector CD8+ T cells. Our study indicates that unequal P2RX7 upregulation in effector CD8+ T cells is a foundational element of the early Tcm/Trm fate. The Journal of Immunology, 2022, 208: 1686-1699.

KW - Animals

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KW - Mice, Inbred C57BL

KW - Receptors, Purinergic P2X7/genetics

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