Regulation of lymphocyte development and function by TRAF2 and TRAF3

Tumour necrosis factor receptor (TNFR) family members are widely expressed in cells of the immune system and are essential for the development and function of many immune cell types. The TNFR associated factor (TRAF) family are signal adapter molecules that are recruited to various members of the TNFR family and are important for the transduction of signals downstream of these receptors. In these studies, gene targeting was used to create a mouse capable of undergoing conditional inactivation of the Traf3 gene. These mice were studied alongside previously generated mice that were similarly genetically modified with respect to the Traf2 gene. The mice produced lacked expression of either TRAF2 or TRAF3 in either B or T cells. In resting B cells TRAF2 and TRAF3 were shown to cooperate to negatively regulate the signalling of B cell activating factor of the TNF family (BAFF) and its receptor (BAFF-R), the TNF ligand and receptor pair that provide obligate survival signals to B cells. Thus, TRAF2- and TRAF3-deficient B cells displayed hyperactive NF-kB2 signalling, an increased ability to survive, and almost identical gene expression profiles, emphasizing the cooperative nature of their roles in resting B cells. Importantly, the survival of these B cells was completely independent of BAFF. In normal B cells, BAFF signalling was shown to lift the negative regulation of survival mediated by TRAF2 and TRAF3, by depleting TRAF3 from the cell. This process was shown to require TRAF2. T cells deficient in TRAF2 or TRAF3 also displayed hyperactivity of the NF-kB2 pathway, but they did not accumulate in vivo or show extended survival in vitro. Mice lacking TRAF2 or TRAF3 in their T cells did however display a decrease in the number of memory phenotype CD8+ T cells. These studies indicate that some of the roles of TRAF2 and TRAF3 are common between B and T cells. However, the consequences of loss of TRAF2 or TRAF3 in B and T cells differs considerably, presumably due to the differential TNFR expression and usage by each cell type