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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.

Original publication




Journal article


Nat immunol

Publication Date





255 - 265


Animals, Calcineurin, Calcium Signaling, Cells, Cultured, Clonal Anergy, DNA-Binding Proteins, Endosomal Sorting Complexes Required for Transport, Isoenzymes, Mice, Mice, Inbred BALB C, Nedd4 Ubiquitin Protein Ligases, Phospholipase C gamma, Protein Kinase C, Protein Kinase C-theta, RNA, Messenger, T-Lymphocytes, Transcription Factors, Type C Phospholipases, Ubiquitin-Protein Ligases, Ubiquitins, Up-Regulation