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CUTTING EDGE |
Is Critical for the Function of CD4+CD25+Foxp3+ Regulatory T Cells1
,
,**
* Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom;
Regulatory T Cell Laboratory, Department of Immunology, Imperial College London, London, United Kingdom;
Department of Veterinary Clinical Sciences, The Royal Veterinary College, Hatfield, United Kingdom;
Cell Signalling Laboratory, Ludwig Institute for Cancer Research, London, United Kingdom;
¶ Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom;
|| GlaxoSmithKline, Stevenage, United Kingdom;
# Department of Medicine, University of Fribourg, Fribourg, Switzerland; and
** Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom
CD4+CD25+Foxp3+ regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance by inhibiting the expansion and function of conventional T cells. Treg development and homeostasis are regulated by the Ag receptor, costimulatory receptors such as CD28 and CTLA-4, and cytokines such as IL-2, IL-10, and TGF-β. Here we show that the proportions of Tregs in the spleen and lymph nodes of mice with inactive p110
PI3K (p110D910A/D910A) are reduced despite enhanced Treg selection in the thymus. p110D910A/D910A CD4+CD25+Foxp3+ Tregs showed attenuated suppressor function in vitro and failed to secrete IL-10. In adoptive transfer experiments, p110D910A/D910A T cells failed to protect against experimental colitis. The identification of p110 as an intracellular signaling protein that regulates the activity of CD4+CD25+Foxp3+ Tregs may facilitate the further elucidation of the molecular mechanisms responsible for Treg-mediated suppression.
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 O.A.G. was supported by a Wellcome Trust Advanced Fellowship. D.T.P. and C.R.M. were supported by Medical Research Council PhD studentships. D.T.P. was also supported by a Collaborative Award in Science and Engineering (CASE) contribution from GlaxoSmithKline. L.C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC)/AstraZeneca CASE studentship. L.S.K.W. was supported by an Medical Research Council Career Development Fellowship. W.P.P. was supported by the Migration and Inflammation Framework VI consortium. B.V. was supported by the Ludwig Institute for Cancer Research. K.O. was supported by a BBSRC David Phillips Fellowship.
2 D.T.P. and O.A.G. made equal contributions to this manuscript.
3 Address correspondence and reprint requests to Dr. Klaus Okkenhaug, Laboratory of Lymphocyte Signalling and Development, Babraham Institute, CB2 4AT Cambridge, United Kingdom. E-mail address: klaus.okkenhaug{at}bbsrc.ac.uk or Dr. Oliver Garden, Regulatory T Cell Laboratory, Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, United Kingdom or Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, United Kingdom. E-mail address: o.garden{at}imperial.ac.uk or ogarden{at}rvc.ac.uk
4 Abbreviations used in this paper: Treg, regulatory T cell; PLN, peripheral lymph node; MLN, mesenteric lymph node; WT, wild type; SAg, superantigen.
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