Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells.
Despite expression of the high-affinity IL-2R, CD4(+)CD25(+) regulatory T cells (Tregs) are hypoproliferative upon IL-2R stimulation in vitro. However the mechanisms by which CD4(+)CD25(+) T cells respond to IL-2 signals are undefined. In this report, we examine the cellular and molecular responses of CD4(+)CD25(+) Tregs to IL-2. IL-2R stimulation results in a G(1) cell cycle arrest, cellular enlargement and increased cellular survival of CD4(+)CD25(+) T cells. We find a distinct pattern of IL-2R signaling in which the Janus kinase/STAT pathway remains intact, whereas IL-2 does not activate downstream targets of phosphatidylinositol 3-kinase. Negative regulation of phosphatidylinositol 3-kinase signaling and IL-2-mediated proliferation of CD4(+)CD25(+) T cells is inversely associated with expression of the phosphatase and tensin homologue deleted on chromosome 10, PTEN.
Bensinger
Steven J
SJ
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Walsh
Patrick T
PT
Zhang
Jidong
J
Carroll
Martin
M
Parsons
Ramon
R
Rathmell
Jeffrey C
JC
Thompson
Craig B
CB
Burchill
Matthew A
MA
Farrar
Michael A
MA
Turka
Laurence A
LA
D000818:Animals; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D006131:Growth Inhibitors; D007376:Interleukin-2; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C487757:Pten protein, mouse