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Unique Phenotype of Human Tonsillar and In Vitro-Induced FOXP3⁺CD8⁺ T Cells¹

Kerstin Siegmund^*, Beate Rückert^*, Nadia Ouaked^*, Simone Bürgler^*, Andreas Speiser, Cezmi A. Akdis^* and Carsten B. Schmidt-Weber^2,

^* Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland; Allergy and Clinical Immunology, National Heart & Lung Institute, Imperial College London, London, United Kingdom; and Spital Davos, Otorhinolaryngology Department, Davos, Switzerland

Forkhead box p3 (FOXP3) is known to program the acquisition of suppressive capacities in CD4⁺ regulatory T cells (Treg), whereas its role in CD8⁺ T cells is unknown. The current study investigates whether FOXP3 also acts as a Treg master switch in peripheral blood and tonsillar CD8⁺ T cells. Single-cell analyses reveal the existence of a FOXP3⁺CD8⁺ population in human tonsils, whereas FOXP3⁺CD8⁺ T cells are rarely detected in peripheral blood. Tonsillar FOXP3⁺CD8⁺ T cells exhibit a Treg phenotype with high CTLA-4 and CD45RO and low CD127 and CD69 expression. Interestingly, the tonsillar FOXP3⁺CD8⁺ T cells are mostly CD25^negative and some cells also express the proinflammatory cytokines TNF-, IFN-, or IL-17A. Particularly, IL-17A-expressing cells are present among FOXP3⁺CD8⁺ T cells. Even though FOXP3 expression is at the detection limit in peripheral blood CD8⁺ T cells ex vivo, it can be induced in vitro in naive CD8⁺ T cells by polyclonal stimulation. The induced FOXP3⁺CD8⁺ T cells are predominantly CD25^high and CD28^high and similar to tonsillar cells, they produce high levels of TNF-, IFN-, and granzyme B. However, IL-4 expression is mutually exclusive and IL-17A expression is not detectable. These FOXP3⁺CD8⁺ T cells suppress the proliferation of CD4⁺ T cells in cocultures, while showing no direct cytotoxic activity. In conclusion, the current study characterizes FOXP3-expressing CD8⁺ T cells from human tonsils and shows that in vitro activation leads to FOXP3 expression in CD8⁺ T cells and gain of suppressive activity.

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 This work was supported in part by a Marie Curie Intra-European Fellowship from the European Commission (to K.S.) and Swiss National Science Foundation Grants 320000-118226 (to C.A.A.) and SNF 310000-112329 (to C.B.SW.).

² Address correspondence and reprint requests to Dr. Carsten B. Schmidt-Weber, Allergy and Clinical Immunology, National Heart & Lung Institute, Imperial College London, SAF building, Room 365, Exhibition Road, London SW7 2AZ, U.K. E-mail address: c.schmidt-weber{at}imperial.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T; RORt, retinoic acid receptor-related orphan receptor t; EF-1, elongation factor 1; FOXP3, forkhead box p3; LDH, lactate dehydrogenase; Fwd, forward; rev, reverse; iTreg, inducible regulatory T cell; ECD, energy-coupled dye.

⁴ The online version of this article contains supplemental material.