Data from Overproduction of IFNγ by Cbl-b–Deficient CD8<sup>+</sup> T Cells Provides Resistance against Regulatory T Cells and Induces Potent Antitumor Immunity

Abstract

<div>Abstract<p>Regulatory T cells (Treg) are an integral component of the adaptive immune system that negatively affect antitumor immunity. Here, we investigated the role of the E3 ubiquitin ligase casitas B-lineage lymphoma-b (Cbl-b) in establishing CD8<sup>+</sup> T-cell resistance to Treg-mediated suppression to enhance antitumor immunity. Transcriptomic analyses suggested that Cbl-b regulates pathways associated with cytokine signaling and cellular proliferation. We showed that the hypersecretion of IFNγ by Cbl-b–deficient CD8<sup>+</sup> T cells selectively attenuated CD8<sup>+</sup> T-cell suppression by Tregs. Although IFNγ production by Cbl-b–deficient T cells contributed to phenotypic alterations in Tregs, the cytokine did not attenuate the suppressive function of Tregs. Instead, IFNγ had a profound effect on CD8<sup>+</sup> T cells by directly upregulating interferon-stimulated genes and modulating T-cell activation. In murine models of adoptive T-cell therapy, Cbl-b–deficient T cells elicited superior antitumor immune response. Furthermore, Cbl-b–deficient CD8<sup>+</sup> T cells were less susceptible to suppression by Tregs in the tumor through the effects of IFNγ. Collectively, this study demonstrates that the hypersecretion of IFNγ serves as a key mechanism by which Cbl-b–deficient CD8<sup>+</sup> T cells are rendered resistant to Tregs.</p><p><i>See related Spotlight by Wolf and Baier, p. 370</i>.</p></div>