Protein Kinase C-η Deficiency Does Not Impair Antiviral Immunity and CD8⁺ T Cell Activation.

ABSTRACT: We reported that protein kinase C-η (PKCη) forms a novel (to our knowledge) signaling complex with the checkpoint inhibitory protein CTLA-4 in regulatory T cells (Tregs). This complex is required for the contact-dependent suppressive activity of Tregs, including suppression of antitumor immunity. However, the importance of PKCη in protective immunity mediated by T effector cells remains unclear. We used mice with germline or conditional Treg-specific deletion of Prkch, the PKCη-encoding gene, to explore CD8⁺ T cell-dependent antiviral immunity using the lymphocytic choriomeningitis virus Armstrong strain acute infection model as well as the in vitro activation of murine or human CD8⁺ T cells. Five days following infection, germline Prkch ^-/- mice displayed enhanced viral clearance compared with control mice. Similarly, Prkch Treg-specific conditional knockout mice also showed improved viral clearance and displayed enhanced expression of granzyme B and IFN-γ by both virus-specific and total CD8⁺ T cells, demonstrating that enhanced viral clearance in germline Prkch ^-/- mice is caused by PKCη deficiency in Tregs and the resulting functional defect of Prkch ^-/- Tregs. In addition, purified Prkch ^-/- mouse CD8⁺ T cells as well as PRKCH knockdown human CD8⁺ T cells displayed intact, or even enhanced, T cell activation in vitro as measured by proliferation and expression of granzyme B and IFN-γ. Thus, global PKCη deletion does not impair overall CD8⁺ T cell-mediated immunity, including antiviral immunity, implying that selective pharmacological PKCη inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor-specific and, likely, virus-specific immunity.

SUBMITTER: Liu HY 

PROVIDER: S-EPMC7373375 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature