Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction.
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 PLCgamma-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells.
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Myung-Shin
MS
Jeon
Alex
A
Atfield
K
K
Venuprasad
Connie
C
Krawczyk
Renu
R
Sarao
Chris
C
Elly
Chun
C
Yang
Sudha
S
Arya
Kurt
K
Bachmaier
Leon
L
Su
Dennis
D
Bouchard
Russel
R
Jones
Mathew
M
Gronski
Pamela
P
Ohashi
Teiji
T
Wada
Debra
D
Bloom
C Garrison
CG
Fathman
Yun-Cai
YC
Liu
Josef M
JM
Penninger
D048868:Adaptor Proteins, Signal Transducing; D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology* / Q000502:physiology; D004768:Enterotoxins / Q000276:immunology; D066298:In Vitro Techniques; D051379:Mice; D051966:Phospholipase C gamma; D050721:Proto-Oncogene Proteins c-cbl; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000276:immunology / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; C118387:Cblb protein, mouse; D004768:Enterotoxins; C031818:enterotoxin B, staphylococcal; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma