Selective inhibition of NF-κB in dendritic cells by the NEMO-binding domain peptide blocks maturation and prevents T cell proliferation and polarization

Abstract

Dendritic cells (DC) are the only antigen-presenting cells for naive T cells and, therefore, they are crucial players in the initiation of immune responses. Because DC maturation and cytokine production are NF-κB dependent, we hypothesized that blocking NF-κB activity in DC by selectively targeting the inhibitor of κB (IκB) kinase (IKK) complex using the novel NF-κB inhibitor NEMO-binding domain (NBD) peptide could inhibit DC maturation and other functional characteristics, resulting in modulation of the immune response. We used human mono cyte-derived DC to test the biological effects of the NBD peptide in vitro. NF-κB inhibition by the NBD peptide resulted in blockade of IKK-mediated IκBα phosphorylation and subsequent nuclear translocation and DNA binding of NF-κB p65 in DC. In addition, IL-6, IL-12, and TNF-α production was dose-dependently blocked and NBD peptide treatment also led to a strong reduction of LPS-induced maturation. Functional analysis of these DC showed marked inhibition of T cell proliferation in the allogeneic mixed lymphocyte reaction, accompanied by less Th1 and Th2 polarization. The current study reveals for the first time the unique properties of this novel, highly specific NF-κB inhibitor in DC. Also, these data indicate that the NBD peptide could be used as an elegant tool in DC based immunotherapy for unwanted cellular immune responses. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.