BioProject

Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. More...

Regulatory T cells are one of the integral components of the adaptive immune system that contribute to the regulation of anti-tumor T cell responses. However, studies have suggested that alterations in T cell signaling networks can result in T cells that are resistant to the suppressive effects of Treg cells. Here, we investigated the role of Cbl-b, an E3 ubiquitin ligase and a negative regulator of TCR signaling pathways, in establishing CD8+ T cell resistance to Treg cell-mediated suppression. First, the absence of Cbl-b rendered CD8+ T cells refractory to the suppressive effects of Treg cells in vitro. Transcriptomic analyses suggested that pathways associated with cellular proliferation and cytokine production likely contribute to the observed phenotype. In particular, hyper-secretion of IFN-g by Cbl-b deficient CD8+ T cells served as a novel mechanism which selectively renders CD8+ T cells less sensitive to suppression by Treg cells. To explore our findings in vivo, we utilized tumor-bearing FoxP3DTR-eGFP mice to confirm that the adoptively transferred tumor-specific CD8+ T cells were susceptible to regulation by Treg cells in the tumor. Unlike the wildtype counterpart, Cbl-b deficient CD8+ T cells were resistant to the suppressive effects of Treg cells in the tumor, and the therapeutic benefit of Cbl-b deficiency was abrogated upon IFN-g blockade. Collectively, our data highlight the role of Cbl-b deficiency and subsequent hyper-secretion of IFN-g as a key mechanism which renders CD8+ T cells resistant to Treg cell-mediated suppression. Overall design: CD8+ T-cells, either CBLB wildtype (WT) or knockout (KO), some stimulated with either anti-CD3 or anti-CD3 + anti-CD28 Less...