Signaling through the NF-kB pathway is of critical importance for T and B lymphocyte maturation, maintenance and function. It is also involved in autoimmune reactions performed by these cells and contributes to the survival of certain classes of B cell lymphomas. Critical components in this pathway are the IkB-kinases (IKKs) which activate NF-kB signaling upon their own activation by pro-inflammatory and antigen receptor mediated signals delivered to the cells. IKK signaling can either involve the IKK signal some consisting of IKK1, IKK2 and the NEMO protein, or proceed through IKK1 activation alone. The underlying hypothesis of the present proposal is that the activation of these two pathways, either in combination or separately, is essential for T and B cells to mature, survive and perform their various functions, and also for the promotion of certain B cell malignancies. We will therefore explore in which way the inactivation of either pathway, or its enforced activation, affect the maturation, functional activities and malignant transformation of T and/or B cells at various stages of development. Rescue experiments will identify the downstream targets of IKK signaling which are responsible for cellular maintenance, and also establish whether IKK signaling is sufficient for cellular survival in the absence of receptors such as the antigen and BAFF receptor, known to be required for B cell maintenance in normal physiology. We will also define the role of cell-autonomous IKK signals in T and B cell mediated autoreactivity. Cell type-specific activation and inactivation of IKKs will be used for this purpose, exploiting techniques of conditional gene targeting which we have established in the past. ? ?
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