A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling

Vigo Heissmeyer, Fernando Macián, Rajat Varma, Sin Hyeog Im, Francisco García-Cozar, Heidi F. Horton, Michael C. Byrne, Stefan Feske, K. Venuprasad, Hua Gu, Yun Cai Liu, Michael L. Dustin, Anjana Rao

Research output: Chapter in Book/Report/Conference proceedingConference contribution

24 Scopus citations

Abstract

In lymphocytes, integration of Ca2+ and other signalling pathways results in productive activation, while unopposed Ca2+ signalling leads to decreased responsiveness to subsequent stimulation (anergy). The Ca2+-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. NFAT cooperates with the transcription factor AP-1 (Fos/Jun) to up-regulate genes involved in productive activation of lymphocytes. However, in the absence of AP-1, NFAT imposes an opposing genetic programme that leads to lymphocyte anergy. Anergy is implemented at least partly through proteolytic degradation of the key signalling proteins PKCθ and PLCγ1. Sustained Ca2+-calcineurin signalling increases mRNA and protein levels of the E3 ubiquitin ligases Itch, CblB and Grail and induces expression of Tsg101, the ubiquitin-binding component of the ESCRT1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promotes membrane translocation of Itch and the related protein Nedd4, resulting in PKCθ and PLCγ1 degradation. T cells from Itch- and CblB-deficient mice are resistant to anergy induction. Anergic T cells show impaired calcium mobilization after TCR triggering and are unable to maintain a mature immunological synapse. Thus Ca2+-calcineurin-NFAT signalling links gene transcription to a multi-step programme that leads to impaired signal transduction in anergic T cells.

Original languageEnglish (US)
Title of host publicationGenetics of Autoimmunity
Pages165-174
Number of pages10
StatePublished - Dec 1 2005

Publication series

NameNovartis Foundation Symposium
Volume267
ISSN (Print)1528-2511

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Heissmeyer, V., Macián, F., Varma, R., Im, S. H., García-Cozar, F., Horton, H. F., Byrne, M. C., Feske, S., Venuprasad, K., Gu, H., Liu, Y. C., Dustin, M. L., & Rao, A. (2005). A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling. In Genetics of Autoimmunity (pp. 165-174). (Novartis Foundation Symposium; Vol. 267).