Protein Kinase C η Is Required for T Cell Activation and Homeostatic Proliferation

Abstract

Protein kinase Cη (PKCη) is highly abundant in T cells and is recruited to the immunological synapse that is formed between a T cell and a cognate antigen-presenting cell; however, its function in T cells is unknown. Here, we showed that PKCη was required for the activation of mature CD8+ T cells by stimulation through the T cell receptor. PKCη−/− T cells showed poor proliferation in response to stimulation by antigen as compared to wild-type T cells, a trait shared with T cells deficient in PKCθ, the most abundant PKC isoform in T cells, and the only PKC previously thought to have a specific role in T cell activation. In contrast, defective homeostatic proliferation, a function requiring recognition of self antigens, was only observed in PKCη- deficient T cells. PKCη was dispensable for the development of thymocytes; however, thymocytes from mice doubly deficient in PKCη and PKCθ exhibited poor positive selection, indicating some redundancy between the PKC isoforms. PKCη and PKCθ had opposing effects on relative numbers of CD4+ and CD8+ T cells, because PKCη−/− mice had a higher ratio of CD4+ to CD8+ T cells compared to that of wild-type mice, whereas PKCθ−/− mice had a lower ratio. In mice deficient in both PKC isoforms, the ratio of CD4+ to CD8+ T cells returned to normal. Together, these data suggest that whereas PKCη shares redundant roles with PKCθ in T cell biology, it also performs nonredundant functions that are important for homeostasis and activation of T cells.

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

“…The top-ranked super-enhancer in both IEL populations is adjacent to Prkch (Fig. S3B), a nonclassical Ca2 + -insensitive η-type PKC that promotes T-cell activation and cytoskeletal polarization (14,15).…”

Calcium mobilization is both required and sufficient for initiating chromatin decondensation during activation of peripheral T-cells

“…This is of particular importance because initially PKCθ was the only isoform found to translocate to the TCR complex following antigen engagement (Monks et al, 1997). Recently, it has been shown that PKCη is also recruited to the immunological synapse and in similar fashion to PKCθ, can regulate [Ca 2+ ] i in T-cells (Fu et al, 2011). The activity of both of these isoforms is required for proper T-cell activation (Fu et al, 2011; Pfeifhofer et al, 2003; Sun et al, 2000).…”

“…Recently, it has been shown that PKCη is also recruited to the immunological synapse and in similar fashion to PKCθ, can regulate [Ca 2+ ] i in T-cells (Fu et al, 2011). The activity of both of these isoforms is required for proper T-cell activation (Fu et al, 2011; Pfeifhofer et al, 2003; Sun et al, 2000). In support of an antagonistic relationship between PKC and IP 3 signaling, we noted that PMA in combination with ionomycin appeared to be less effective than ionomycin alone in decondensing chromatin in our solubility assays (Figure 1C).…”

Protein kinase C inhibitors for immune disorders

“…By sharp contrast, we found recently that PKCη-deficient ( Prkch −/− ) mice exhibit a moderately immune hyperreactive phenotype indicative of an important function in T cell homeostasis (unpublished data). Prkch −/− mice that develop mild lymphadenopathy contain circulating autoantibodies, and their memory T cells display enhanced production of cytokines such as interleukin (IL)-2, IL-4 and IL-17A upon CD3/CD28 stimulation [6]. We further demonstrated that the regulatory T (Treg) cells of Prkch −/− mice are impaired in their contact-dependent suppressive activity in vitro and in vivo (unpublished data), indicating that PKCηplays a crucial part in at least one effector mechanism utilized by Treg cells and, hence, in the maintenance of T cell tolerance.…”