Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins.

Journal article

Sustained 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 Ca(2+)-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-theta and PLC-gamma1. 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.

Authors: Heissmeyer, V; Macián, F; Im, S; Varma, R; Feske, S

• Journal: Nature immunology
• Volume: 5
• Issue: 3
• Pages: 255-265
• Publication date: 2004-03-01
• DOI: 10.1038/ni1047
• EISSN: 1529-2916
• ISSN: 1529-2908
• Language: English
• Keywords: Animals; Ubiquitin-Protein Ligases; Up-Regulation; Protein Kinase C; Clonal Anergy; Ubiquitins; RNA, Messenger; T-Lymphocytes; Calcium Signaling; Phospholipase C gamma; Cells, Cultured; Calcineurin; DNA-Binding Proteins; Mice, Inbred BALB C; Isoenzymes; Endosomal Sorting Complexes Required for Transport; Transcription Factors; Type C Phospholipases; Mice