Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins

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

Research output: Contribution to journalArticle

416 Citations (Scopus)

Abstract

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
Volume5
Issue number3
DOIs
StatePublished - Mar 2004

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Calcineurin
Proteolysis
T-Lymphocytes
Proteins
Immunological Synapses
Calcium
Lymphocyte Function-Associated Antigen-1
Calcium Signaling
Ubiquitin
Cell Adhesion
Signal Transduction
Transcription Factors
Antigens
Messenger RNA
Membranes
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. / Heissmeyer, Vigo; Macian-Juan, Fernando; Im, Sin Hyeog; Varma, Rajat; Feske, Stefan; Venuprasad, K.; Gu, Hua; Liu, Yun Cai; Dustin, Michael L.; Rao, Anjana.

In: Nature Immunology, Vol. 5, No. 3, 03.2004, p. 255-265.

Research output: Contribution to journalArticle

Heissmeyer, V, Macian-Juan, F, Im, SH, Varma, R, Feske, S, Venuprasad, K, Gu, H, Liu, YC, Dustin, ML & Rao, A 2004, 'Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins', Nature Immunology, vol. 5, no. 3, pp. 255-265. https://doi.org/10.1038/ni1047
Heissmeyer, Vigo ; Macian-Juan, Fernando ; Im, Sin Hyeog ; Varma, Rajat ; Feske, Stefan ; Venuprasad, K. ; Gu, Hua ; Liu, Yun Cai ; Dustin, Michael L. ; Rao, Anjana. / Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. In: Nature Immunology. 2004 ; Vol. 5, No. 3. pp. 255-265.
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