Overproduction of IL-2 by Cbl-b deficient CD4+ T cells provides resistance against regulatory T cells

• Main Authors: SeongJun Han, Douglas C. Chung, Michael St. Paul, Zhe Qi Liu, Carlos Garcia-Batres, Alisha R. Elford, Charles W. Tran, Laurence Chapatte, Pamela S. Ohashi
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2020-01-01
• Series: OncoImmunology
• Subjects: immune regulation; t cell; treg; cytokine
• Online Access: http://dx.doi.org/10.1080/2162402X.2020.1737368

Regulatory T cells are integral to the regulation of autoimmune and anti-tumor immune responses. However, several studies have suggested that changes in T cell signaling networks can result in T cells that are resistant to the suppressive effects of regulatory T cells. Here, we investigated the role of Cbl-b, an E3 ubiquitin ligase, in establishing resistance to Treg-mediated suppression. We found that the absence of Cbl-b, a negative regulator of multiple TCR signaling pathways, rendered T cells impartial to Treg suppression by regulating cytokine networks leading to improved anti-tumor immunity despite the presence of Treg cells in the tumor. Specifically, Cbl-b KO CD4+FoxP3− T cells hyper-produced IL-2 and together with IL-2 Rα upregulation served as an essential mechanism to escape suppression by Treg cells. Furthermore, we report that IL-2 serves as the central molecule required for cytokine-induced Treg resistance. Collectively our data emphasize the role of IL-2 as a key mechanism that renders CD4+ T cells resistant to the inhibitory effects of Treg cells.