CD4+CD25+ regulatory T cells attenuate the phosphatidylinositol 3-kinase/Akt pathway in antigen-primed immature CD8+ CTLs during functional maturation.
This study was designed to determine the role of CD25(+)CD4(+) regulatory T (Tr) cells in CTL maturation and effector functions using a murine CTL line and in vitro MLC. Tr cells inhibited CTL functional maturation, but had no effect on CTL effector functions. In CD4(+) responder T cell-depleted MLC supplemented with IL-2, Tr cells suppressed mature CTL generation only when added within the first 2 days of culture. Tr cells down-regulated levels of active Akt, but not STAT5 or ZAP70 in Ag-primed immature CTLs. Down-regulation of active Akt was accompanied by a reduction in CTL cell size and IL-2Ralpha expression. In Tr cell-depleted MLC, CTLs were generated that exhibited high levels of nonspecific cytotoxicity. Our in vitro findings suggest that Tr cells regulate functional CTL maturation to generate optimal Ag-specific immune responses through the control of the PI3K/Akt pathway.
Kojima
Hidefumi
H
Department of Immunology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. hkojima@dokkyomed.ac.jp
Kanno
Yumiko
Y
Hase
Hidenori
H
Kobata
Tetsuji
T
D000818:Animals; D000941:Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D048429:Cell Size; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed / Q000379:methods; D008212:Lymphocyte Depletion; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D015534:Trans-Activators / Q000096:biosynthesis; D051746:ZAP-70 Protein-Tyrosine Kinase
D000941:Antigens; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse