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Although dendritic cells (DCs) are the most potent antigen-presenting cells involved in numerous physiologic and pathologic processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function. Recently, we demonstrated that nuclear factor (NF)-kappaB activation is central to that process, as overexpression of IkappaBalpha blocks the allogeneic mixed lymphocyte reaction (MLR), an in vitro model of T-cell activation. In this study, we investigated the role of 2 putative NF-kappaB-inducing components, NF-kappaB-inducing kinase (NIK), and IkappaB kinase 2 (IKK2). Using an adenoviral gene transfer method to efficiently express dominant-negative (dn) forms of these molecules in monocyte-derived DCs, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR. When DCs were fixed, this inhibitory effect of IKK2dn was lost, suggesting that IKK2 is involved in T-cell-derived signals that enhance DC antigen presentation during the allogeneic MLR period and does not have an effect on viability or differentiation state of DCs prior to coculture with T cells. One such signal is likely to be CD40 ligand (CD40L), as IKK2dn blocked CD40L but not lipopolysaccharide (LPS)-induced NF-kappaB activation, cytokine production, and up-regulation of costimulatory molecules and HLA-DR in DCs. In summary, our results demonstrate that IKK2 is essential for DC activation induced by CD40L or contact with allogeneic T cells, but not by LPS, whereas NIK is not required for any of these signals. In addition, our results support IKK2 as a potential therapeutic target for the down-regulation of unwanted immune responses that may occur during transplantation or autoimmunity.

Original publication

DOI

10.1182/blood-2002-06-1835

Type

Journal article

Journal

Blood

Publication Date

02/2003

Volume

101

Pages

983 - 991

Addresses

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom.

Keywords

Dendritic Cells, T-Lymphocytes, Animals, Humans, Mice, Adenoviridae, Protein-Serine-Threonine Kinases, Lipopolysaccharides, NF-kappa B, CD40 Ligand, Lymphocyte Culture Test, Mixed, Immunosuppression, Transduction, Genetic, Lymphocyte Activation, Signal Transduction, Antigen Presentation, I-kappa B Kinase