The role of p100 and ReIB in B lymphopoiesis

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The NF-KB signal transduction pathway is known to be involved in innate and adaptive immune responses, inflammatory processes, the regulation of apoptosis and cancer. Recent reports indicate that NF-KB family members also control the development of T and B cells. However, it is not fully established whether NF-KB has important cell-autonomous functions in the development of early lymphocytes: that is before the expression of the pre-T cell receptor (pre- TCR) or the pre-B cell receptor (pre-BCR). In the proposed project we would like to investigate early B cell development in mice that lack the inhibitory p100 precursor of p52/NF-KB2. p100 has been shown to specifically block RelB and to play an important role in the activation of RelB/NF-KB via the recently described alternative pathway. Our initial results indicate that B cell development in pWO mice is arrested at the pro-B stage due to dramatically reduced Pax5 expression. After a more detailed characterization of the B cell developmental block in plOtf mice we plan to examine whether increased constitutive activation of RelB is responsible for the impaired B lymphopoiesis and whether B cell-specific and lineage-inappropriate genes are differentially expressed in B cell precursors from wild-type and p100^ mice. Since p100-deficient mice have myeloid hyperplasia and Pax5 represses myeloid-specific genes we also want to examine the lympho-myeloid differentiation potential of pWO^ pro-B cells. Finally, we attempt to rescue the B cell developmental block in p10Gf~ mice by ectopic expression of a Pax5 transgene. These studies should result in a better understanding of the role of NF-KB, in particular of p100, RelB, and the alternative pathway, in early B cell development.