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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.

SUBMITTER: Borges da Silva H

PROVIDER: S-EPMC8026201 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Borges da Silva Henrique H Peng Changwei C Wang Haiguang H Wanhainen Kelsey M KM Ma Chaoyu C Lopez Sharon S Khoruts Alexander A Zhang Nu N Jameson Stephen C SC

Immunity 20200707 1

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 reside ...[more]

PMID: 32640257

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Project description:Expression of programmed cell death-1 receptor (PD-1) has traditionally been linked to T-cell exhaustion, as signaling via PD-1 dampens the functionality of T-cells upon repetitive antigen exposures during chronic infections. However, resent findings pointing to the involvement of PD-1 both in T-cell survival and in restraining immunopathology, challenge the concept of PD-1 solely as marker for T-cell exhaustion. Tissue resident memory T cells (Trms) hold unique effector qualities, but within a delicate organ like the CNS, these protective abilities could potentially be harmful. In contrast to their counterparts in many other tissues, brain derived CD8+ Trms have been found to uniformly and chronically express PD-1. In this study we utilized a recently established model system for generating CNS Trms in order to improve our understanding regarding the role of PD-1 expression by Trms inside the CNS. By intracerebral (i.c.) inoculation with a non-replicating adeno-viral vector, we induced a PD-1hi CD8+ T cell memory population within the CNS. We found that PD-1 expression lowered the severity of clinical disease associated with the i.c. inoculation. Furthermore, high levels of PD-L1 expression were found on the infiltrating monocytes and macrophages as well as on the resident microglia, oligodendrocytes and astrocytes during the acute phase of the response. Additionally, we showed that the intensity of PD-1 expression correlates with local antigen encounter and found that PD-1 expression was associated with decreased CD8+ T cell memory formation in the CNS despite an increased number of infiltrating CD8+ T cells. Most importantly, our experiments revealed that despite expression of PD-1 and several additional markers linked to T-cell exhaustion, Tim-3, Lag-3 and CD39, the cells did not show signs of limited effector capacity. Collectively, these results endorse the increasing amount of evidence pointing to an immune-modifying role for PD-1 expression within the CNS, a mechanism we found to correlate with local antigen exposure.

Dataset Information

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

Publications

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

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Dataset Information

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

Publications

Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8&lt;sup&gt;+&lt;/sup&gt; Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β.

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OmicsDI is part of the ELIXIR infrastructure

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

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