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Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells1
,
* Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom;
Ludwig Institute for Cancer Research, London, United Kingdom;
GlaxoSmithKline, Stevenage, United Kingdom; and
Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom
The role of PI3K in T cell activation and costimulation has been controversial. We previously reported that a kinase-inactivating mutation (D910A) in the p110
isoform of PI3K results in normal T cell development, but impaired TCR-stimulated cell proliferation in vitro. This proliferative defect can be overcome by providing CD28 costimulation, which raises the question as to whether p110 activity plays a role in T cell activation in vivo, which occurs primarily in the context of costimulation. In this study, we show that the PI3K signaling pathway in CD28-costimulated p110D910A/D910A T cells is impaired, but that ERK phosphorylation and NF-
B nuclear translocation are unaffected. Under in vitro conditions of physiological Ag presentation and costimulation, p110D910A/D910A T cells showed normal survival, but underwent fewer divisions. Differentiation along the Th1 and Th2 lineages was impaired in p110D910A/D910A T cells and could not be rescued by exogenous cytokines in vitro. Adoptive transfer and immunization experiments in mice revealed that clonal expansion and differentiation in response to Ag and physiological costimulation were also compromised. Thus, p110 contributes significantly to Th cell expansion and differentiation in vitro and in vivo, also in the context of CD28 costimulation.
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 by grants from the Biotechnology and Biological Sciences Research Council (to K.O. and B.V.), the Ludwig Institute for Cancer Research, and European Union Framework V (to B.V.). K.O. is a Biotechnology and Biological Sciences Research Council David Phillips Fellow. D.T.P. was supported by a Medical Research Council and GlaxoSmithKline Co-Operative Award in Science and Engineering.
2 Address correspondence and reprint requests to Dr. Klaus Okkenhaug, Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, CB2 4AT, U.K. E-mail address: klaus.okkenhaug{at}bbsrc.ac.uk
3 Abbreviations used in this paper: LAT, linker for activation of T cells; 7-AAD, 7-aminoactinomycin D; PdBu, phorbol-12,13-dibutyrate; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; WT, wild type.
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