ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells.
Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25(+)CD4(+) regulatory T cell (T(R)) assays mainly in activated Foxp3(-) effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25(-)CD4(+) T cells antagonizes T(R)-mediated suppression. Moreover, forced expression of Foxp3 in naive CD25(-) T cells induces constitutive expression of ICER/CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/CREM both in Foxp3 transductants as well as CD25(-) responder T cells suggesting that induction of T(R) function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25(-) responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligand-bearing Foxp3(-) effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T(R) cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/CREM expression in activated CD25(+) Foxp3(-) T cell effectors thus preventing them from producing IL-2.
Bodor
Josef
J
Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. jb2562@columbia.edu
Fehervari
Zoltan
Z
Diamond
Betty
B
Sakaguchi
Shimon
S
D000818:Animals; D002478:Cells, Cultured; D051786:Cyclic AMP Response Element Modulator / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
C497411:Crem protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator