E3
ubiquitin ligases have been placed among the essential molecules involved in the
regulation of
T cell functions and
T cell tolerance. However, it has never been experimentally proven in vivo whether these functions indeed depend on the catalytic
E3 ligase activity. The Casitas
B-cell lymphoma (Cbl)
family protein Cbl-b was the first
E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral
T cell. In this study, we
report that selective genetic inactivation of Cbl-b
E3 ligase activity phenocopies the
T cell responses observed when total Cbl-b is ablated, resulting in
T cell hyperactivation, spontaneous
autoimmunity, and impaired induction of
T cell anergy in vivo. Moreover,
mice carrying a Cbl-b
E3 ligase-defective
mutation spontaneously reject
tumor cells that express
human papilloma virus Ags. These data demonstrate for the first
time, to our
knowledge, that the catalytic function of an
E3 ligase, Cbl-b, is essential for negative
regulation of
T cells in vivo. Thus, modulation of the
E3 ligase activity of Cbl-b might be a novel modality to control
T cell immunity in
vaccination,
cancer biology, or
autoimmunity(AU)