Protein kinase C-eta (PKCη) is dispensable for the activation and function of CD8+T cells

Abstract

Abstract We previously reported that protein kinase C-eta (PKCη) forms a novel signaling complex with CTLA4 in regulatory T cells (Tregs) and this complex is required for the contact-dependent suppressive activity of Tregs. As a result, PKCη-deficient (Prkch−/−) Tregs fail to suppress anti-tumor immunity. However, given the ubiquitous expression of PKCη, it has remained unclear whether PKCη is also required for the effector functions of conventional T cells, particularly CD8+T cells that play a critical role in anti-tumor immunity. We therefore assessed the effect of genetic PKCη deletion on CD8+T cell-dependent immune functions. We found that Prkch−/− mouse or PRKCH knockdown human CD8+T cells displayed intact, and even enhanced, T cell activation in vitro as measured by proliferation and expression of TNFα, IFNγ, and granzyme B (GzmB) following anti-CD3 plus -CD28 costimulation. Next, we used the acute LCMV infection as an in vivo model to study the characteristics of virus-specific CD8+T cells, which were identified by specific staining with CD8 tetramers. Splenocytes from Prkch−/− mice showed similar frequencies of tetramer+CD8+T cells to those of wild-type (WT) mice, and these cells proliferated normally and expressed normal levels of TNFα and IFNγ. The LCMV-specific Prkch−/−CD8+T cells expressed normal or increased levels of GzmB, and the infected mice displayed greater viral clearance. We conclude that PKCη deficiency does not impact the activation and function of CD8+T cells. Taken together, the selective inhibition of the CTLA4-PKCη signaling pathway in cancer patients is a promising therapeutic strategy to inactivate tumor-promoting Tregs and, thus, enhance anti-tumor immunity, without having adverse effects on CD8+T cells.