The distinction of self from non-self is crucial to prevent autoreactivity and assure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among them, the E3 ligase ubiquitin casitas B cell lymphoma-b (Cbl-b) is a newly identified component in the ubiquitin-dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program coordinated by Cbl-b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers, and other immunopathologic conditions. In the present review, the latest findings were comprehensively summarized on the molecular structural basis of Cbl-b, the suppressive signaling mechanisms of Cbl-b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.
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