Transcriptional mechanisms underlying lymphocyte tolerance.
In lymphocytes, integration of Ca2+ and other signaling pathways results in productive activation, while unopposed Ca2+ signaling leads to tolerance or anergy. We show that the Ca2+-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. Ca2+/calcineurin signaling induces a limited set of anergy-associated genes, distinct from genes induced in the productive immune response; these genes are upregulated in vivo in tolerant T cells and are largely NFAT dependent. T cells lacking NFAT1 are resistant to anergy induction; conversely, NFAT1 induces T cell anergy if prevented from interacting with its transcriptional partner AP-1 (Fos/Jun). Thus, in the absence of AP-1, NFAT imposes a genetic program of lymphocyte anergy that counters the program of productive activation mediated by the cooperative NFAT:AP-1 complex.
Macián
Fernando
F
Center for Blood Research, Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
García-Cózar
Francisco
F
Im
Sin-Hyeog
SH
Horton
Heidi F
HF
Byrne
Michael C
MC
Rao
Anjana
A
D000818:Animals; D018106:CD28 Antigens / Q000096:biosynthesis; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division; D002614:Chelating Agents / Q000494:pharmacology; D017635:Clonal Anergy; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D015759:Ionomycin / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012190:Retroviridae / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
D018106:CD28 Antigens; D002614:Chelating Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015759:Ionomycin; D019703:Calcineurin; D002118:Calcium