Nature Immunology
5, 255 - 265 (2004)
Published online: 15 February 2004; | doi:10.1038/ni1047
Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteinsVigo Heissmeyer1, Fernando Macián1, 5, Sin-Hyeog Im1, 5, Rajat Varma2, Stefan Feske1, K Venuprasad3, Hua Gu4, Yun-Cai Liu3, Michael L Dustin2
& Anjana Rao11
Center for Blood Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA. 2
Program in Molecular Pathogenesis and Department of Pathology, Skirball Institute of Molecular Medicine, New York University School of Medicine, New York, New York 10016, USA. 3
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA. 4
Department of Microbiology, Columbia University, College of Physicians and Surgeons, 701 West 168th Street, HHSC, New York, New York 10032, USA. 5
Present addresses: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA (F.M.) and Department of Life Science, Kwangju Institute of Science and Technology, 1 Oryong-dong, Puk-ku, Kwangju 500-712, Korea (S.-H.I.).
Correspondence should be addressed to Anjana Rao arao@cbr.med.harvard.eduSustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca2+-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC- and PLC- 1. T cells from Itch- and Cbl-b−deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function−associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
