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

doi:10.1016/j.immuni.2004.07.013

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 journal › Article › peer-review

289 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 language	English (US)
Pages (from-to)	167-177
Number of pages	11
Journal	Immunity
Volume	21
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2004.07.013
State	Published - Aug 2004
Externally published	Yes

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

Jeon, MS, 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, CG, Liu, YC & Penninger, JM 2004, 'Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction', Immunity, vol. 21, no. 2, pp. 167-177. https://doi.org/10.1016/j.immuni.2004.07.013

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title = "Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction",

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.",

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

note = "Funding Information: We thank A. Altman, K. Sugie, H. Tabata, Y. Tanaka, and other colleagues at the Division of Cell Biology for support and discussions; K. Hu for technical assistance; M. Naramura and H. Gu for Cbl-b −/− mice and suggestions; T. Watts and P. Liu for helpful discussions; and F-F. Liu for kind help. A.A. is supported by a University of Toronto open fellowship. This work is supported by grants to Y.-C.L. from the National Institutes of Health (grants RO1AI50280 and RO156558) and a biomedical research grant from the Arthritis Foundation and by grants to J.M.P. from the Canadian Institute of Health Research (CIHR), Euro-Thymaide (6. EU framework), the National Bank of Austria, and the Austrian Academy of Science. J.M.P. holds equity in a company that attempts to make cbl-b inhibitors.",

year = "2004",

month = aug,

doi = "10.1016/j.immuni.2004.07.013",

language = "English (US)",

volume = "21",

pages = "167--177",

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T1 - Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction

AU - Jeon, Myung Shin

AU - Atfield, Alex

AU - Venuprasad, K.

AU - Krawczyk, Connie

AU - Sarao, Renu

AU - Elly, Chris

AU - Yang, Chun

AU - Arya, Sudha

AU - Bachmaier, Kurt

AU - Su, Leon

AU - Bouchard, Dennis

AU - Jones, Russel

AU - Gronski, Mathew

AU - Ohashi, Pamela

AU - Wada, Teiji

AU - Bloom, Debra

AU - Fathman, C. Garrison

AU - Liu, Yun Cai

AU - Penninger, Josef M.

N1 - Funding Information: We thank A. Altman, K. Sugie, H. Tabata, Y. Tanaka, and other colleagues at the Division of Cell Biology for support and discussions; K. Hu for technical assistance; M. Naramura and H. Gu for Cbl-b −/− mice and suggestions; T. Watts and P. Liu for helpful discussions; and F-F. Liu for kind help. A.A. is supported by a University of Toronto open fellowship. This work is supported by grants to Y.-C.L. from the National Institutes of Health (grants RO1AI50280 and RO156558) and a biomedical research grant from the Arthritis Foundation and by grants to J.M.P. from the Canadian Institute of Health Research (CIHR), Euro-Thymaide (6. EU framework), the National Bank of Austria, and the Austrian Academy of Science. J.M.P. holds equity in a company that attempts to make cbl-b inhibitors.

PY - 2004/8

Y1 - 2004/8

N2 - 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.

AB - 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.

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ER -

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

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