Role of PKCθ in T-cell signalling

Abstract

Sun, Z. et al. (2000) PKCθ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407T-cell signalling and subsequent cytokine gene expression is dependent on the activation of members of the serine/threonine-specific protein kinase C (PKC) family. Conventional PKCs are activated by both diacylglycerol (DAG) and Ca2+. PKCθ, along with the δ, ϵ and η enzymes, is a member of the ‘novel’ subclass of PKCs that are activated by DAG only. PKCθ is expressed only in T cells and is rapidly recruited to the contact point between the T cell and the APC. In this study, Sun et al. generated a PKCθ-knockout mouse and examined the role of PKCθ in TCR signalling.FACS analysis studies indicated that cell numbers in the thymus, spleen and lymph nodes of PKCθ−/− mice were normal, and the processes of negative and positive selection in the thymus did not require PKCθ.Peripheral T-cell signalling was found to be dependent on PKCθ. Purified T cells were stimulated to proliferate using plate-bound anti-CD3 antibody, with or without anti-CD28 stimulation. In comparison with wild-type mice, proliferation of T cells from PKC−/− mice was significantly reduced. This was also true of T cells stimulated to proliferate in mixed lymphocyte reactions. FACS analysis studies showed that the reduced proliferative responses of PKCθ T cells was due to decreased expression of both interleukin 2 (IL-2) and the high-affinity IL-2 receptor.The induction of cytokine gene expression following T-cell signalling is dependent on several transcription factors, including NF-AT, AP-1 and NF-κB. The absence of PKCθ had no effect on the translocation of NF-AT1 and 2 to the nucleus after activation of wild-type and PKCθ−/− T cells. Mature PKCθ T cells showed a significant defect in the activation of NF-κB activation following stimulation with anti-CD3, or anti-CD3 plus anti-CD28. By contrast, NF-κB activation was unaffected in activated PKCθ−/− thymocytes, suggesting that an alternative PKC enzyme is important for T-cell signalling in thymocytes.This study indicates that PKCθ is important in linking T-cell signalling and NF-κB activation in a unique signalling pathway in mature T cells.