The Role of Cbl-b in CD4+ T Cell Resistance to Regulatory T Cell Suppression

Cancer immunotherapy has demonstrated enormous potential as a novel therapeutic modality in the management of multiple malignancies, including melanoma and leukemia. While cancer immunotherapy is designed to enhance effector T cell function and promote tumor destruction, one of its limitations is the negative influence of tumour-resident CD4 + FoxP3 + regulatory T (Treg) cells on T cell anti-tumour activity. Previous attempts to overcome this challenge have largely focused on the depletion of Treg cells, but this has proven to be a challenging and largely ineffectual process. An alternative approach to overcoming this problem involves generating effector T cell resistance against Treg cell-mediated suppression. Work in this area to date has shown that deficiency in the E3 ubiquitin ligase, Cbl-b, in mice results in the development of hyper-proliferative and pro-inflammatory effector T cells, even in the presence of Treg cells. This study investigates the cellular mechanisms behind this Treg resistance using Cbl-b deficient CD4 + FoxP3 − and CD8 + T cells. We demonstrate that Cbl-b −/− CD4 + FoxP3 − T cells exhibit both hyper-secretion of and hyper-sensitivity to IL-2, and that this serves as an important mechanism to escape suppression by Treg cells. Accordingly, we show that the blockade of IL-2Rα is sufficient to reverse the Treg cell-mediated suppression and excess IL-2 alone is sufficient to override suppressive signals by Treg cells. Overall, this study provides further insight into the potential development of Treg resistant effector T cells able to generate a more robust anti-tumor immune response.