Extracellular ATP Limits Homeostatic T Cell Migration Within Lymph Nodes.

Akira Takeda,Shinsuke Matsuzaki,Tomoya Katakai,Sirpa Jalkanen,Marko Salmi,Yuki Sugiura,Gennady G Yegutkin,Masayuki Miyasaka,Eiji Umemoto,Itaru Hamachi,Daichi Kobayashi,Makoto Suematsu,Haruko Hayasaka,Hisashi Ueta

doi:10.3389/fimmu.2021.786595

Abstract

Whereas adenosine 5’-triphosphate (ATP) is the major energy source in cells, extracellular ATP (eATP) released from activated/damaged cells is widely thought to represent a potent damage-associated molecular pattern that promotes inflammatory responses. Here, we provide suggestive evidence that eATP is constitutively produced in the uninflamed lymph node (LN) paracortex by naïve T cells responding to C-C chemokine receptor type 7 (CCR7) ligand chemokines. Consistently, eATP was markedly reduced in naïve T cell-depleted LNs, including those of nude mice, CCR7-deficient mice, and mice subjected to the interruption of the afferent lymphatics in local LNs. Stimulation with a CCR7 ligand chemokine, CCL19, induced ATP release from LN cells, which inhibited CCR7-dependent lymphocyte migration in vitro by a mechanism dependent on the purinoreceptor P2X7 (P2X7R), and P2X7R inhibition enhanced T cell retention in LNs in vivo. These results collectively indicate that paracortical eATP is produced by naïve T cells in response to constitutively expressed chemokines, and that eATP negatively regulates CCR7-mediated lymphocyte migration within LNs via a specific subtype of ATP receptor, demonstrating its fine-tuning role in homeostatic cell migration within LNs.

Highlights

adenosine 5’-triphosphate (ATP) serves as the major energy source in cells and once released from the cell, it provides strong inflammatory signals even at low concentrations, whereas its metabolite, adenosine, provides antiinflammatory signals, through specific purinergic receptors expressed on the surface of cells [1,2,3,4]
Consistent with these findings, enzyme histochemical analysis showed that ATPase and ADPase were abundant in the T cell area of resting lymph node (LN), whereas AMPase was less abundant but still localized in T cell areas (Figure 1B)
These observations are compatible with the idea that extracellular ATP (eATP) is constitutively produced in the T cell area of uninflamed LNs but is degraded mainly in situ by ecto-nucleotidases constitutively expressed on dendritic cells and T cells in the same area

Summary

Introduction

ATP serves as the major energy source in cells and once released from the cell, it provides strong inflammatory signals even at low concentrations, whereas its metabolite, adenosine, provides antiinflammatory signals, through specific purinergic receptors expressed on the surface of cells [1,2,3,4]. Isolated T cells were shown to produce eATP subsequent to antigenic stimulation [8,9,10,11,12], which resulted in the autocrine stimulation of specific ATP receptors expressed on T cells, leading to enhanced T cell activation [8]. These results further strengthen the idea that ATP is a proinflammatory molecule that enhances immune responses upon release from the cell. To the best of our knowledge, no experimental study has verified the presence or absence of eATP in uninflamed immunological tissues or its role in homeostasis

Methods

Results

Conclusion