Protein Kinase C-η Deficiency Does Not Impair Antiviral Immunity and CD8

We reported that protein kinase C-eta (PKCη) forms a novel 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 anti-tumor immunity. However, the importance of PKCη in protective immunity mediated by T effector (Teff) 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 to control mice. Similarly, Prkch Treg-specific conditional knockout (cKO) mice also showed improved viral clearance and displayed enhanced expression of granzyme B (GzmB) and interferon-γ (IFNγ) 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 GzmB and IFNγ. 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.