Immunology Saved from Destruction

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Survival of naïve B lymphocytes depends on the cytokine BAFF (B cell-activating factor of the tumor necrosis factor family). Although BAFF can signal through several receptors, only one of them (BAFF-R) is essential for survival (see Cancro). Noting that BAFF-R binds TNF receptor-associated factor 3 (TRAF3) and that TRAF3 and TRAF2 have been implicated in B cell survival, Gardam et al. examined the effects on lymphocyte survival of lineage-specific inactivation of TRAF2 or TRAF3 or both. Mice lacking B cell TRAF2 (Traf2B mice) or B cell TRAF3 (Traf3B mice) showed an indistinguishable phenotype, characterized by increased numbers of lymph node and splenic marginal zone B cells, that resembled that of mice overexpressing BAFF (BAFF-tg mice). B cells from Traf2B and Traf3B mice survived in vitro in the absence of BAFF and, like BAFF-tg B cells, showed increased activation of the alternative (noncanonical) NF-B (nuclear factor B) signaling pathway. No further effects on B cell phenotype were seen when both TRAF2 and TRAF3 were absent, and microarray analysis revealed that mature B cells from Traf2B and Traf3B mice showed nearly identical gene expression profiles, which were similar to those of BAFF-tg B cells. Elimination of TRAF2 from the B cells rescued B cell development in BAFF-deficient mice. The abundance of TRAF3 protein (but not Traf3 mRNA) was increased in B cells from mice lacking BAFF, BAFF-R, or TRAF-2. The authors thus propose that BAFF acts as a survival factor by stimulating TRAF2-dependent TRAF3 depletion and reversing the cooperative TRAF2- and TRAF3-dependent inhibition of B cell survival.

S. Gardam, F. Sierro, A. Basten, F. Mackay, R. Brink, TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity 28, 391-401 (2008). [PubMed]

M. P. Cancro, Living in context with the survival factor BAFF. Immunity 28, 300-301 (2008). [PubMed]