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Regulatory T Cells Are Resistant to Apoptosis via TCR but Not P2X₇¹

Simon R. J. Taylor^*, Denis R. Alexander, Joanne C. Cooper, Christopher F. Higgins^* and James I. Elliott^2,*

^* Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, U.K.; and Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge, U.K.

Regulatory T cells (Tregs) are relatively autoreactive yet, paradoxically, have been found to display normal sensitivity to thymic deletion. The relationship between self-avidity, apoptosis, and the selection of Tregs therefore remains unclear. We show that thymic Tregs develop efficiently, even at low self-avidity, and are moderately resistant to apoptosis in comparison to conventional thymocytes. Consistent with this, although conventional self-reactive T cell populations undergo chronic peripheral deletion, self-reactive Tregs are largely spared removal. Similarly, the distribution of Tregs among peripheral CD4⁺ cells exhibits a linear inverse relationship with CD45RB expression, indicating relative apoptosis resistance of Tregs in chronic responses to environmental Ags. We also show that appropriate controls for CD45RB levels are important for comparisons of Treg and conventional T cell activity. When thus controlled, and contrary to previous reports, Tregs exhibit normal sensitivity to cell death through TCR-independent stimuli, such as the purinergic receptor, P2X₇. Finally, although absence of CD45 in gene-targeted mice results in profound T cell hyporesponsiveness, there is little or no effect on thymic Treg frequency. In summary, the data support a model in which signal strength plays little part in Treg lineage specification, though moderate resistance of self-reactive Tregs to apoptosis may result in progressive biasing of peripheral Treg TCRs toward autoreactivity in comparison to those of conventional T cells.

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 funded by the Medical Research Council, U.K.

² Address correspondence and reprint requests to Dr. James Elliott, Membrane Transport Biology Group, Medical Research Council Clinical Sciences Centre, Du Cane Road, London, U.K. E-mail address: james.elliott{at}csc.mrc.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; Mtv sags, mouse mammary tumor virus superantigens; FSC, forward light scatter; PS, phosphatidylserine; SP, single positive.

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