TY - JOUR
T1 - E3 ubiquitin ligase Cbl-b regulates thymic-derived CD4+CD25+ regulatory T cell development by targeting Foxp3 for ubiquitination
AU - Zhao, Y.
AU - Guo, H.
AU - Qiao, G.
AU - Zucker, M.
AU - Langdon, Wallace
AU - Zhang, J.
PY - 2015
Y1 - 2015
N2 - Copyright © 2015 by The American Association of Immunologists, Inc. CD28 costimulation is essential for the development of thymic-derived CD4+CD25+Foxp3+ regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28-/- mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28-/-T cells, the defective development of tTregs in Cd28-/- mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28-/- mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development.
AB - Copyright © 2015 by The American Association of Immunologists, Inc. CD28 costimulation is essential for the development of thymic-derived CD4+CD25+Foxp3+ regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28-/- mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28-/-T cells, the defective development of tTregs in Cd28-/- mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28-/- mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development.
U2 - 10.4049/jimmunol.1402434
DO - 10.4049/jimmunol.1402434
M3 - Article
C2 - 25560411
SN - 0022-1767
VL - 194
SP - 1639
EP - 1645
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -