Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells.
CD4+CD25+Foxp3+ regulatory T cells (Tregs) contribute to the maintenance of peripheral tolerance by inhibiting the expansion and function of conventional T cells. Treg development and homeostasis are regulated by the Ag receptor, costimulatory receptors such as CD28 and CTLA-4, and cytokines such as IL-2, IL-10, and TGF-beta. Here we show that the proportions of Tregs in the spleen and lymph nodes of mice with inactive p110delta PI3K (p110deltaD910A/D910A) are reduced despite enhanced Treg selection in the thymus. p110deltaD910A/D910A CD4+CD25+Foxp3+ Tregs showed attenuated suppressor function in vitro and failed to secrete IL-10. In adoptive transfer experiments, p110deltaD910A/D910A T cells failed to protect against experimental colitis. The identification of p110delta as an intracellular signaling protein that regulates the activity of CD4+CD25+Foxp3+ Tregs may facilitate the further elucidation of the molecular mechanisms responsible for Treg-mediated suppression.
Patton
Daniel T
DT
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.
Garden
Oliver A
OA
Pearce
Wayne P
WP
Clough
Louise E
LE
Monk
Clare R
CR
Leung
Eva
E
Rowan
Wendy C
WC
Sancho
Sara
S
Walker
Lucy S K
LS
Vanhaesebroeck
Bart
B
Okkenhaug
Klaus
K
D000818:Animals; D020134:Catalytic Domain / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007376:Interleukin-2 / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006131:Growth Inhibitors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases