Ikappa B kinase 2 but not NF-kappa B-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction
| Autor: | Clive Smith, Brian M. J. Foxwell, Marc Feldmann, Fionula M. Brennan, Claudia Monaco, Evangelos Andreakos |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Lipopolysaccharides
T-Lymphocytes medicine.medical_treatment CD40 Ligand Immunology Antigen presentation chemical and pharmacologic phenomena Protein Serine-Threonine Kinases Lymphocyte Activation Biochemistry Adenoviridae Immune tolerance Mice Transduction Genetic medicine Animals Humans Immunosuppression Therapy Antigen Presentation CD40 biology NF-kappa B I-Kappa-B Kinase hemic and immune systems Dendritic Cells Cell Biology Hematology Dendritic cell Mixed lymphocyte reaction I-kappa B Kinase Cell biology Transplantation Cytokine biology.protein Lymphocyte Culture Test Mixed Signal Transduction |
| Popis: | 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)-κB activation is central to that process, as overexpression of IκBα 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-κB–inducing components, NF-κB–inducing kinase (NIK), and IκB 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-κB 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. |
| Databáze: | OpenAIRE |
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