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PTEN inhibits IL-2 receptor–mediated expansion of CD4+ CD25+ Tregs
Patrick T. Walsh, … , Wayne W. Hancock, Laurence A. Turka
Patrick T. Walsh, … , Wayne W. Hancock, Laurence A. Turka
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2521-2531. https://doi.org/10.1172/JCI28057.
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Research Article Immunology

PTEN inhibits IL-2 receptor–mediated expansion of CD4+ CD25+ Tregs

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Abstract

One of the greatest barriers against harnessing the potential of CD4+CD25+ Tregs as a cellular immunotherapy is their hypoproliferative phenotype. We have previously shown that the hypoproliferative response of Tregs to IL-2 is associated with defective downstream PI3K signaling. Here, we demonstrate that targeted deletion of the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) regulates the peripheral homeostasis of Tregs in vivo and allows their expansion ex vivo in response to IL-2 alone. PTEN deficiency does not adversely affect either the thymic development or the function of Tregs, which retain their ability to suppress responder T cells in vitro and prevent colitis in vivo. Conversely, reexpression of PTEN in PTEN-deficient Tregs as well as in activated CD4+ T cells inhibits IL-2–dependent proliferation, confirming PTEN as a negative regulator of IL-2 receptor signaling. These data demonstrate that PTEN regulates the “anergic” response of Tregs to IL-2 in vitro and Treg homeostasis in vivo and indicate that inhibition of PTEN activity may facilitate the expansion of these cells for potential use in cellular immunotherapy.

Authors

Patrick T. Walsh, Jodi L. Buckler, Jidong Zhang, Andrew E. Gelman, Nicole M. Dalton, Devon K. Taylor, Steven J. Bensinger, Wayne W. Hancock, Laurence A. Turka

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Figure 4

Reexpression of PTEN in PTEN-ΔT Tregs restores hypoproliferative response to IL-2.

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Reexpression of PTEN in PTEN-ΔT Tregs restores hypoproliferative respons...
Purified PTEN-ΔT CD4+CD25+CD45RBlo cells were CFSE labeled and retrovirally transduced as described in Methods, with either MIGR1-NGFR empty vector (ev-NGFR) or PTEN-containing virus (PTEN-NGFR). Cells were analyzed for expression of human NGFR 96 hours after infection and CFSE dilution of NGFR-positive cells analyzed by flow cytometry. Results are representative of 3 independent experiments. SSC, side scatter.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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