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More MS news articles for November 2002

I{kappa}B kinase 2 but not NF-{kappa}B-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction

Blood 2002 Sep 19
Andreakos E, Smith C, Monaco C, Brennan FM, Foxwell BM, Feldmann M.

Although dendritic cells (DC) are the most potent antigen-presenting cells involved in numerous physiological and pathological processes, little is known about the signaling pathways that regulate DC activation and antigen-presenting function.

Recently, we demonstrated that 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 two 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 DC, we found that IKK2dn but not NIKdn inhibited the allogeneic MLR.

When DC 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 rather than an effect on viability or differentiation state of DC prior to coculture with T cells.

One such signal is likely to be CD40 ligand (CD40L) as IKK2dn blocked CD40L but not LPS-induced NF-kappaB activation, cytokine production and up-regulation of costimulatory molecules and HLA-DR in DC.

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.