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High Sensitivity of Intestinal CD8⁺ T Cells to Nucleotides Indicates P2X7 as a Regulator for Intestinal T Cell Responses¹

Kirsten Heiss^*, Nathalie Jänner^,, Birgit Mähnß^*, Valéa Schumacher^*, Friedrich Koch-Nolte^*, Friedrich Haag^* and Hans-Willi Mittrücker^2,*,

^* Institute for Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Medical Faculty, Kiel, Germany; and Max Planck Institute for Infection Biology, Berlin, Germany

The purinoreceptor P2X7 is expressed on subsets of T cells and mediates responses of these cells to extracellular nucleotides such as ATP or NAD⁺. We identified P2X7 as a molecule highly up-regulated on conventional CD8β⁺ and unconventional CD8⁺ T cells of the intestinal epithelium of mice. In contrast, CD8⁺ T cells derived from spleen, mesenteric lymph nodes, and liver expressed only marginal levels of P2X7. However, P2X7 was highly up-regulated on CD8⁺ T cells from spleen and lymph nodes when T cells were activated in the presence of retinoic acid. High P2X7 expression on intestinal CD8⁺ T cells as well as on CD8⁺ T cells incubated with retinoic acid resulted in enhanced sensitivity of cells to extracellular nucleotides. Both cell populations showed a high level of apoptosis following incubation with NAD⁺ and the ATP derivative 2',3'-O-(benzoyl-4-benzoyl)-ATP, and injection of NAD⁺ caused selective in vivo depletion of intestinal CD8⁺ T cells. Following oral infection with Listeria monocytogenes, P2X7-deficient mice showed similar CD8⁺ T cell responses in the spleen, but enhanced responses in the intestinal mucosa, when compared with similarly treated wild-type control mice. Overall, our observations define P2X7 as a new regulatory element in the control of CD8⁺ T cell responses in the intestinal mucosa.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ F.K.-N. and F.H. were supported by the Deutsche Forschungsgemeinschaft (DFG NO310/6-2).

² Address correspondence and reprint requests to Dr. Hans-Willi Mittrücker, Institute for Immunology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany. E-mail address: h.mittruecker{at}uke.de

³ Abbreviations used in this paper: ART, ADP-ribosyltransferase; BzATP, 2',3'-O-(benzoyl-4-benzoyl)-ATP; LmOVA, Listeria monocytogenes recombinant for ovalbumin; MLN, mesenteric lymph node; PI, propidium iodide; PS, phosphatidylserine; Treg, regulatory T.