GRAIL is up-regulated in CD4+ CD25+ T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype.
GRAIL (gene related to anergy in lymphocytes) is an ubiquitin-protein isopeptide ligase (E3) ubiquitin ligase necessary for the induction of CD4(+) T cell anergy in vivo. We have extended our previous studies to characterize the expression pattern of GRAIL in other murine CD4(+) T cell types with a described anergic phenotype. These studies revealed that GRAIL expression is increased in naturally occurring (thymically derived) CD4(+) CD25(+) T regulatory cells (mRNA levels 10-fold higher than naive CD25(-) T cells). Further investigation demonstrated that CD25(+) Foxp3(+) antigen-specific T cells were induced after a "tolerizing-administration" of antigen and that GRAIL expression correlated with the CD25(+) Foxp3(+) antigen-specific subset. Lastly, using retroviral transduction, we demonstrated that forced expression of GRAIL in a T cell line was sufficient for conversion of these cells to a regulatory phenotype in the absence of detectable Foxp3. These data demonstrate that GRAIL is differentially expressed in naturally occurring and peripherally induced CD25(+) T regulatory cells and that the expression of GRAIL is linked to their functional regulatory activity.
MacKenzie
Debra A
DA
Department of Pediatrics, Division of Allergy/Immunology/Rheumatology, University of Wisconsin, Madison, Wisconsin 53792.
Schartner
Jill
J
Department of Pediatrics, Division of Allergy/Immunology/Rheumatology, University of Wisconsin, Madison, Wisconsin 53792.
Lin
Jack
J
Department of Medicine, Division of Immunology/Rheumatology, Stanford University, Stanford, California 94305.
Timmel
Amanda
A
Department of Pediatrics, Division of Allergy/Immunology/Rheumatology, University of Wisconsin, Madison, Wisconsin 53792.
Jennens-Clough
Martha
M
Department of Pediatrics, Division of Allergy/Immunology/Rheumatology, University of Wisconsin, Madison, Wisconsin 53792.
Fathman
C Garrison
CG
Department of Medicine, Division of Immunology/Rheumatology, Stanford University, Stanford, California 94305.
Seroogy
Christine M
CM
Department of Pediatrics, Division of Allergy/Immunology/Rheumatology, University of Wisconsin, Madison, Wisconsin 53792. Electronic address: cmseroogy@wisc.edu.
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D017635:Clonal Anergy; D016130:Immunophenotyping; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases