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


ABSTRACT: 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 R? 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.

SUBMITTER: Han S 

PROVIDER: S-EPMC7153846 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Overproduction of IL-2 by Cbl-b deficient CD4<sup>+</sup> T cells provides resistance against regulatory T cells.

Han SeongJun S   Chung Douglas C DC   St Paul Michael M   Liu Zhe Qi ZQ   Garcia-Batres Carlos C   Elford Alisha R AR   Tran Charles W CW   Chapatte Laurence L   Ohashi Pamela S PS  

Oncoimmunology 20200407 1


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 cell  ...[more]

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