T helper cell-specific regulation of inducible costimulator expression via distinct mechanisms mediated by T-bet and GATA-3.
Inducible costimulator (ICOS) expression is critical for T cell-mediated immunity. We showed previously that T cell receptor and CD28 co-engagement up-regulate ICOS expression in activated T cells via the induction of NFATc2. Here, we examined the regulation of ICOS expression by Th-specific transcription factors T-bet and GATA-3. Overexpression of T-bet or GATA-3 alone could enhance, and NFATc2 could further synergize with either of them to increase, icos transcription. Although T-bet acted on the icos promoter, GATA-3 operated via an icos 3'-un-translated region element. Interestingly, NFATc2 was found to bind promiscuously the icos promoter in developing Th0, Th1, and Th2 cells but became selectively associated with T-bet at the promoter and with GATA-3 at the 3'-untranslated region in fully differentiated Th1 and Th2 cells, respectively. Collectively, our results reveal a temporally evolving circuit in which the non-selectively expressed NFATc2 cooperates with Th-restricted T-bet or GATA-3 to direct transcription of a costimulatory gene via distinct regulatory elements in different Th cells undergoing differentiation.
Tan
Andy Hee-Meng
AH
Singapore Immunology Network Laboratory of Immune Regulation, Agency for Science, Technology and Research, Biopolis 138648, Singapore.
Goh
Sharon Yun-Pei
SY
Singapore Immunology Network Laboratory of Immune Regulation, Agency for Science, Technology and Research, Biopolis 138648, Singapore.
Wong
Siew-Cheng
SC
Singapore Immunology Network Laboratory of Immune Regulation, Agency for Science, Technology and Research, Biopolis 138648, Singapore.
Lam
Kong-Peng
KP
Singapore Immunology Network Laboratory of Immune Regulation, Agency for Science, Technology and Research, Biopolis 138648, Singapore. Electronic address: lam_kong_peng@immunol.a-star.edu.sg.
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
D020413:3' Untranslated Regions; D000945:Antigens, Differentiation, T-Lymphocyte; D050990:GATA3 Transcription Factor; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor