The extracellular ATP receptor P2RX7 imprints a pro-memory transcriptional signature in effector CD8+ T cells

Vardam-Kaur, T. et al. (BioRxiv) DOI: 10.1101/2021.05.25.445679

 

Keywords

  • Memory T cell

  • P2RX7 signalling

  • Transcriptomics

 

Main Findings

Immunological memory is crucial for individuals to eliminate the pathogens which they have experienced before. Understanding the molecular mechanism of how memory T cells are formed can improve the vaccination efficacy in people with a compromised immune system. In this non-peer-reviewed preprint, Vardam-Kaur et al. showed that P2RX7 signalling pathway contributes to the formation of memory T cells. 

 

Environmental ATPs (eATP) are usually considered danger signals passively released by dying cells. Some cells express P2X purinergic receptors to sense the signal, which can further modulate their functions and cell fates. P2X purinergic receptor 7 (P2RX7) is an eATP-gated ion channel expressed in different immune populations. High expression of P2RX7 in both central memory (Tcm) and tissue-resident memory (Trm) CD8+ T cells are crucial for the maintenance in both cell types. It is still elusive whether P2RX7 signalling plays a role in immunological memory formation in CD8+ T cells, which is addressed by this preprint.

 

Early effector T cells can divide asymmetrically, which gives rise to both memory precursors (MP) and terminal effectors (TTE). Compared to TTE, MP shows a higher level of P2rx7 expression. The expression level of P2RX7 is heterogeneous within MPs. P2RX7hi MPs show expression of markers related to memory T cells, whereas P2RX7loMPs are high in effector-related surface markers. Cell-transfer experiment validated that P2RX7hi MPs is prone to memory formation than P2RX7lo counterparts. Transcriptomic profiling of wild type versus P2rx7-/- and P2RX7hiversus P2RX7lo CD8+ T cells indicates that P2RX7 signalling promotes the expression of a pro-memory gene signature. Zeb2 (Zinc finger E-box-binding homeobox 2), a transcription factor related to effector T cell differentiation, was found to be upregulated in both P2RX7lo and P2rx7-/- CD8+ T cells. Deleting Zeb2 in P2rx7-deficient CD8+ T cell partially restored their capacity to form both Tcm and Trm, suggesting that Zeb2 downregulation is a potential target of P2RX7-eATP-sensing.

Limitations

  • The preprint did not address when and how the differential expression level of P2RX7 is built within the memory precursor population

  • It still needs further investigation that how P2RX7 interplays with some intracellular pathways already known to affect asymmetric cell division, e.g., TCF-1 and PI3K/AKT/mTOR axis.

  • Though Vardam-Kaur et al. suggest that the expression of Zeb2 is controlled by P2RX7 signalling, potentially mediated by TGF-β, more molecular targets of P2RX7 needs to be elucidated. 

Significance/Novelty

The upregulation of P2RX7 expression appears early in effector T cells. It implies the environmental ATP signalling as an extracellular determinant of cell fate, in parallel with the mTOR signalling and TCF-1, two cell-intrinsic factors contribute to the memory T cell formation. This preprint expands the knowledge of how asymmetric cell division takes effect. Moreover, the research suggests some potential therapeutic targets, which can be specific to T cells, to boost the establishment of immunological memory. It can be applied to improve the efficacy of vaccination in aged or immune-compromised individuals.

Credit

Reviewed by Dingxi Zhou as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.