Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins

Vigo Heissmeyer, Fernando Macián, Sin Hyeog Im, Rajat Varma, Stefan Feske, K. Venuprasad, Hua Gu, Yun Cai Liu, Michael L. Dustin, Anjana Rao

Research output: Contribution to journalArticlepeer-review

449 Scopus citations


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 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-θ and PLC-γ1. 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 languageEnglish (US)
Pages (from-to)255-265
Number of pages11
JournalNature Immunology
Issue number3
StatePublished - Mar 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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