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

We reported that protein kinase C-eta (PKC eta) 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 PKC eta in protective immunity mediated by T effector cells remains unclear. We used mice with germline or conditional Treg-specific deletion of Prkch, the PKC eta-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-gamma by both virus-specific and total CD8(+) T cells, demonstrating that enhanced viral clearance in germline Prkch (-/)-mice is caused by PKCh 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-gamma. Thus, global PKCh deletion does not impair overall CD8(+) T cell-mediated immunity, including antiviral immunity, implying that selective pharmacological PKCh 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.