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

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 5

PTEN-ΔT CD4+ CD25+ CD45RBlo cells remain hypoproliferative to TCR stimulation.

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PTEN-ΔT CD4+ CD25+ ...
(A) Purified PTEN-ΔT or wild-type CD4+CD25+CD45RBlo cells were CFSE labeled and stimulated with plate-bound anti-CD3 (5 μg/ml) for 72 hours. (B) Supernatants were harvested under the conditions described above after 24 hours stimulation, and levels of IL-2 were determined by ELISA. Data shown represent the mean ± SD of triplicate samples. Data are representative of 3 separate experiments. (C) Purified PTEN-ΔT or wild-type CD4+CD25+CD45RBlo cells were stimulated with IL-2 (100 U/ml), irradiated APCs, and varying doses of anti-CD3 (2C11) as shown for 72 hours. Tritiated thymidine was added to cultures for the final 16 hours before harvesting. Data shown represent the mean ± SD of triplicate samples. WT25+, CD4+CD25+CD45RBlo cells from wild-type mice; ΔT25+, CD4+CD25+CD45RBlo cells from PTEN-ΔT mice; WT25–, CD4+CD25–CD45RBhi cells from wild-type mice; ΔT25–, CD4+CD25–CD45RBhi cells from PTEN-ΔT mice.