Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction

Myung Shin Jeon, Alex Atfield, K. Venuprasad, Connie Krawczyk, Renu Sarao, Chris Elly, Chun Yang, Sudha Arya, Kurt Bachmaier, Leon Su, Dennis Bouchard, Russel Jones, Mathew Gronski, Pamela Ohashi, Teiji Wada, Debra Bloom, C. Garrison Fathman, Yun Cai Liu, Josef M. Penninger

Research output: Contribution to journalArticle

256 Scopus citations

Abstract

Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCγ-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells.

Original languageEnglish (US)
Pages (from-to)167-177
Number of pages11
JournalImmunity
Volume21
Issue number2
DOIs
StatePublished - Aug 2004
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Jeon, M. S., Atfield, A., Venuprasad, K., Krawczyk, C., Sarao, R., Elly, C., Yang, C., Arya, S., Bachmaier, K., Su, L., Bouchard, D., Jones, R., Gronski, M., Ohashi, P., Wada, T., Bloom, D., Fathman, C. G., Liu, Y. C., & Penninger, J. M. (2004). Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity, 21(2), 167-177. https://doi.org/10.1016/j.immuni.2004.07.013