title: Modulation of Immune Cell Functions by the E3 Ligase Cbl-b.
abstract: Maintenance of immunological tolerance is a critical hallmark of the immune system. Several signaling checkpoints necessary to balance activating and inhibitory input to immune cells have been described so far, among which the E3 ligase Cbl-b appears to be a central player. Cbl-b is expressed in all leukocyte subsets and regulates several signaling pathways in T cells, NK cells, B cells, and different types of myeloid cells. In most cases, Cbl-b negatively regulates activation signals through antigen or pattern recognition receptors and co-stimulatory molecules. In line with this function, cblb-deficient immune cells display lower activation thresholds and cblb knockout mice spontaneously develop autoimmunity and are highly susceptible to experimental autoimmunity. Interestingly, genetic association studies link CBLB-polymorphisms with autoimmunity also in humans. Vice versa, the increased activation potential of cblb-deficient cells renders them more potent to fight against malignancies or infections. Accordingly, several reports have shown that cblb knockout mice reject tumors, which mainly depends on cytotoxic T and NK cells. Thus, targeting Cbl-b may be an interesting strategy to enhance anti-cancer immunity. In this review, we summarize the findings on the molecular function of Cbl-b in different cell types and illustrate the potential of Cbl-b as target for immunomodulatory therapies.
authors: Department of Hematology and Oncology, Medical University Innsbruck , Innsbruck , Austria ; Tumor Immunology Laboratory, Tyrolean Cancer Research Institute , Innsbruck , Austria.
authors: Christina
authors: C
authors: Lutz-Nicoladoni
authors: Medical Clinic III for Oncology, Haematology and Rheumatology, University Clinic Bonn (UKB) , Bonn , Germany.
authors: Dominik
authors: D
authors: Wolf
authors: Department of Hematology and Oncology, Medical University Innsbruck , Innsbruck , Austria ; Tumor Immunology Laboratory, Tyrolean Cancer Research Institute , Innsbruck , Austria.
authors: Sieghart
authors: S
authors: Sopper
keywords: adoptive cell transfer; autoimmunity; cancer; immunotherapy; ubiquitination