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* Department of Immunology;
Kellogg School of Science and Technology Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA 92037; and
ICOS, Bothell, WA 98021
PI3K plays key roles in cell growth, differentiation, and survival by generating the second messenger phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). PIP3 activates numerous enzymes, in part by recruiting them from the cytosol to the plasma membrane. We find that in immature B lymphocytes carrying a nonautoreactive Ag receptor, PI3K signaling suppresses RAG expression and promotes developmental progression. Inhibitors of PI3K signaling abrogate this positive selection. Furthermore, immature primary B cells from mice lacking the p85
regulatory subunit of PI3K suppress poorly RAG expression, undergo an exaggerated receptor editing response, and, as in BCR-ligated cells, fail to progress into the G1 phase of cell cycle. Moreover, immature B cells carrying an innocuous receptor have sustained elevation of PIP3 levels and activation of the downstream effectors phospholipase C (PLC)
2, Akt, and Bruton’s tyrosine kinase. Of these, PLC2 appears to play the most significant role in down-regulating RAG expression. It therefore appears that when the BCR of an immature B cell is ligated, PIP3 levels are reduced, PLC2 activation is diminished, and receptor editing is promoted by sustained RAG expression. Taken together, our results provide evidence that PI3K signaling is an important cue required for fostering development of B cells carrying a useful BCR.
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 research and training grants from the National Institutes of Health (RO1AI33608 to D.N., T32HL07195 to D.A.-A., and Graduate Training Grant F31AI52484).
2 Current address: Human Vaccine Institute, Duke University Medical Center, 106 Research Drive, 4086 MSRBII, Durham, NC 27710.
3 Address correspondence and reprint requests to Dr. David Nemazee, Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, Mail Drop IMM-29, La Jolla, CA 92037. E-mail address: nemazee{at}scripps.edu
4 Abbreviations used in this paper: sIg, surface Ig; Btk, Bruton’s tyrosine kinase; int, intermediate; PH, pleckstrin homology; PIP3, phosphatidylinositol-(3,4,5)-trisphosphate; PLC, phospholipase C; Tg, transgenic.
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