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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-06-1835.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 983-991
IMMUNOBIOLOGY
I B kinase 2 but not NF-B-inducing kinase is essential for
effective DC antigen presentation in the allogeneic mixed
lymphocyte reaction
Evangelos Andreakos,
Clive Smith,
Claudia Monaco,
Fionula M. Brennan,
Brian M. Foxwell, and
Marc Feldmann
From the Kennedy Institute of Rheumatology Division,
Faculty of Medicine, Imperial College of Science, Technology and
Medicine, London, United Kingdom.
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)- B activation is
central to that process, as overexpression of IB 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-B-inducing components, NF-B-inducing kinase (NIK), and IB
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-B 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.
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