Cutting Edge: Cbl-b: One of the Key Molecules Tuning CD28- and CTLA-4-Mediated T Cell Costimulation

Abstract

Cbl-b negatively regulates CD28-dependent T cell activation. In this report, we tested the hypothesis that CD28 and CTLA-4 have opposite roles in tuning T cell activation threshold by controlling the levels of Cbl-b protein expression. We demonstrate that CD28 costimulation potentiates TCR-induced Cbl-b degradation, whereas CTLA-4-B7 interaction is required for Cbl-b re-expression. In support of this finding, Cbl-b expression in CTLA-4 knockout (KO) T cells is significantly reduced, and treating CTLA-4KO mice with human CTLA-4Ig to block CD28-B7 interaction restores Cbl-b expression on T cells. Furthermore, CD28 and CTLA-4 costimulatory effects are compromised in Cbl-bKO T cells. These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation.

T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b

“…We have demonstrated that Cbl-b is one of the key regulators that influences the threshold for T-cell activation regulated by CD28 and CTLA-4 (27,54). This notion is supported by the recent findings that Cbl-b plays a crucial role in the induction of T-cell anergy (14,18).…”

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

“…Taken together, there is strong evidence to support that there are several defects in the ubiquitination profile of T regs from patients with SLE which contribute to resistance to suppression, a phenomenon that is not confined to effector T cell abnormalities. Cbl-b seems to be necessary for the correct inhibitory function of CTLA-4 [51] and PD-1 [52]. Moreover, other E3 ubiquitin ligases have been implicated in resistance to suppression by T regs , such as stress-induced phosphoprotein 1 (STIP1) homology and Ubox-containing protein-1 (Stub1), which interacts with FoxP3 to promote its K48-linked (K48) polyubiquitination [53].…”

Controlling NF-κB activation in T cells by costimulatory receptors

“…While CD28 signalling results in increased Cbl-b ubiquitination/degradation, activation of CTLA-4 signalling increases the amount of Cbl-b. 87 The E3 ligase Itch can not only catalyze ubiquitination and degradation of PLCg and Bcl10, but also causes depletion of the AP-1 family members JunB and c-Jun upon TCR/CD28 engagement. 88 Thus, Itch can interfere at multiple levels with lymphocyte activation, which is in agreement with the profound immunological disorders that are caused through ablation of Itch in mice.…”