Nature Immunology
5, 45 - 54 (2003)
Published online: 7 December 2003; | doi:10.1038/ni1017
Two isoforms of otubain 1 regulate T cell anergy via GRAILLuis Soares1, 2, Christine Seroogy1, 3, Heidi Skrenta1, Niroshana Anandasabapathy1, Patricia Lovelace2, Chan D Chung1, Edgar Engleman2
& C Garrison Fathman11
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California
94305, USA. 2
Department of Pathology, Stanford University School of Medicine, 800 Welch Road, Palo Alto, California
94304, USA. 3
Present address: University of Wisconsin, Department of Pediatrics, Madison, Wisconsin
53792, USA.
Correspondence should be addressed to C Garrison Fathman cfathman@stanford.eduThe active ubiquitin E3 ligase GRAIL is crucial in the induction of CD4 T cell anergy. Here we show that GRAIL is associated with and regulated by two isoforms of the ubiquitin-specific protease otubain 1. In lethally irradiated mice reconstituted with bone marrow cells from T cell receptor−transgenic mice retrovirally transduced to express the genes encoding these proteases, otubain 1−expressing cells contained negligible amounts of endogenous GRAIL, proliferated well and produced large amounts of interleukin 2 after antigenic stimulation. In contrast, cells expressing the alternatively spliced isoform, otubain 1 alternative reading frame 1, contained large amounts of endogenous GRAIL and were functionally anergic, and they proliferated poorly and produced undetectable interleukin 2 when stimulated in a similar way. Thus, these two proteins have opposing epistatic functions in controlling the stability of GRAIL expression and the resultant anergy phenotype in T cells.
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