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Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function

Nature Immunology volume 4, pages 287–294 (2003)Cite this article

Abstract

Phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) phosphatase serve essential functions in the regulation of cell growth, differentiation and survival by modulating intracellular phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3) concentrations. Here we show that the conditional deletion of Pten in B cells led to the preferential generation of marginal zone (MZ) B cells and B1 cells. PTEN-deficient B cells were hyperproliferative in response to mitogenic stimuli, and exhibited a lower threshold for activation through the B cell antigen receptor. Inactivation of PTEN rescued germinal center, MZ B and B1 cell formation in CD19−/− mice, arguing that recruitment and activation of PI3K are the dominant roles for CD19 in these B cell subpopulations. These findings establish the central role of PI-3,4,5-P3 regulation in the differentiation of peripheral B cell subsets.

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Figure 1: Generation of Cd19Cre+/−PtenloxP/loxP mice.
Figure 2: Altered B cell differentiation in Cd19Cre+/−PtenloxP/loxP mice.
Figure 3: Impaired migration, increased basal Rac activity and intact adhesion of PTEN-deficient splenic B cells.
Figure 4: Enhanced Akt activation and in vitro proliferation of PTEN-deficient splenic B cells.
Figure 5: Altered cell cycle progression and survival of PTEN-deficient B cells.
Figure 6: Restoration of MZ B cells, B1 and GC formation in Cd19Cre−/−PtenloxP/loxP mice.

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Acknowledgements

We thank G. Bokoch (The Scripps Research Institute) for providing anti-Rac1, Rac2 antisera; M. David for discussions and members of the Rickert lab for critical evaluation of the manuscript. Supported by National Institutes of Health Grant AI41649 (to R.C.R.) and by a grant from the University of California Cancer Research Coordinating Committee (to R.C.R.). A.N.A. was supported by the Cell, Molecular and Genetic Training Program Grant (NIH, GM07246).

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  1. Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0322, La Jolla, 92093, CA, USA

    Amy N. Anzelon & Robert C. Rickert

  2. UCSD Cancer Center, University of California, San Diego, 9500 Gilman Drive, MC 0322, La Jolla, 92093, CA, USA

    Amy N. Anzelon & Robert C. Rickert

  3. Department of Molecular and Medical Pharmacology, University of California at Los Angeles School of Medicine, Los Angeles, 90095, CA, USA

    Hong Wu

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Correspondence to Robert C. Rickert.

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Anzelon, A., Wu, H. & Rickert, R. Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nat Immunol 4, 287–294 (2003). https://doi.org/10.1038/ni892

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