Immature CD4+CD8+ thymocytes and mature T cells regulate Nur77 distinctly in response to TCR stimulation.
The orphan steroid receptor, Nur77, is thought to be a central participant in events leading to TCR-mediated clonal deletion of immature thymocytes. Interestingly, although both immature and mature murine T cell populations rapidly up-regulate Nur77 after TCR stimulation, immature CD4+CD8+ thymocytes respond by undergoing apoptosis, whereas their mature descendants respond by dividing. To understand these developmental differences in susceptibility to the proapoptotic potential of Nur77, we compared its regulation and compartmentalization and show that mature, but not immature, T cells hyperphosphorylate Nur77 in response to TCR signals. Nur77 resides in the nucleus of immature CD4+CD8+ thymocytes throughout the course of its expression and is not found in either the organellar or cytoplasmic fractions. However, hyperphosphorylation of Nur77 in mature T cells, which is mediated by both the MAPK and PI3K/Akt pathways, shifts its localization from the nucleus to the cytoplasm. The failure of immature CD4+CD8+ thymocytes to hyperphosphorylate Nur77 in response to TCR stimulation may be due in part to decreased Akt activity at this developmental stage.
Cunningham
Nicole R
NR
Department of Biology, Haverford College, Haverford, PA 19041, USA.
Artim
Stephen C
SC
Fornadel
Christen M
CM
Sellars
Maclean C
MC
Edmonson
Samuel G
SG
Scott
Grant
G
Albino
Frank
F
Mathur
Akriti
A
Punt
Jennifer A
JA
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018106:CD28 Antigens / Q000502:physiology; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D005260:Female; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
D018106:CD28 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt