Recent work by others has provided evidence that, in contrast to conventional T cells, PKCq negatively regulates the suppressive activity of Treg cells. Therefore, we initiated efforts to identify other member(s) of the PKC enzyme family, which might positively regulate Treg cell function. This work resulted in the identification of protein kinase C-eta (PKCh) as being required for contact-dependent Treg cell suppressive activity. Furthermore, Treg cell costimulation via the TCR and CTLA4, a major Treg cell-expressed inhibitory receptor required for most suppression pathways, resulted in a direct association between the CTLA4 intracellular domain and PKCh. As a result, strategies that blocked the CTLA4-PKCh interaction impaired the suppressive activity of Treg cells. Interestingly, PKCh-deficient Treg cells lost their ability to inhibit immune response against growing mouse tumors, but retained their ability to inhibit the development of a model autoimmune disease in mice, i.e., adoptive T cell transfer-mediated colitis. Additionally, we found that PKCh-deficient Treg cells display reduced motility and prolonged arrest on antigen-presenting dendritic cells (DC) in vivo, resulting in defective overall depletion of costimulatory DC ligands, an effect that is consistent with reduced suppressive activity and enhanced tumor immunity. We continue to study the mechanistic aspects of this novel signaling pathway, and the applicability of manipulating it in order to enhance tumor-specific immunity.