E3 Ubiquitin Ligase Riplet Is Expressed in T Cells and Suppresses T Cell-Mediated Antitumor Immune Responses

The E3 ubiquitin ligase Riplet mediates retinoic acid-inducible gene-I polyubiquitination and is essential for viral-induced expression of type I IFNs in dendritic cells and macrophages. The function of Riplet in innate immunity has been well demonstrated; however, its role in adaptive immunity during the antitumor immune response is unclear. In this study, we examined the role of Riplet in the T cell-mediated antitumor immune response. Riplet was expressed in T cells and upregulated in CD8(+) T cells in response to TCR-mediated stimulation. Furthermore, PR domain containing 1, eomesodermin, and killer cell lectinlike receptor G1 expression was increased in effector CD8(+) T cells by Riplet knockout in vitro, which suggests that Riplet is involved in the effector function of CD8(+) T cells. Our results indicated that Riplet deficiency augmented the antitumor response of MO4 (OVA-expressing melanoma)-bearing mice treated with OVA peptide-pulsed dendritic cells. Moreover, both CD4(+) and CD8(+) T cells played important roles in Riplet-mediated augmentation of the antitumor immune response. In tumor-draining lymph nodes, the Th1 response was promoted, and the induction of OVA-specific CD8(+) T cells and IFN-gamma production were enhanced by Riplet deficiency. Furthermore, the IFN-gamma response and OVA-specific cytotoxicity of CD8(+) T cells in tumor tissue were augmented by Riplet deficiency. The expression of Cxcl9fluorescence-minus-one and Cxcl10 mRNA was also enhanced in the tumor microenvironment by Riplet knockout, consistent with the augmented recruitment of CTLs. Overall, we clarified a function of Riplet in T cells, which is to suppress the antitumor immune response through modulating Th1 and CTLs.

Automated summary

The study reveals that Riplet plays a suppressive role in the antitumor immune response mediated by T cells. Riplet deficiency enhances the antitumor immune response by modulating Th1 and CTLs.