Regulation of B-Cell Self-Tolerance By BAFF and the Molecular Basis of Its Action
Signals delivered following the binding of BAFF to its receptor BAFF-R are essential for the survival of mature conventional B cells. In order to maintain self-tolerance, B cells that express antigen receptors with significant reactivity against self-antigens are prevented from receiving or responding to these survival signals. The great majority of B cells produced from bone marrow precursors fail to join the mature peripheral B cell pool due either to their self-reactivity or to a stochastic failure to receive adequate survival signals from the limiting levels of BAFF available in vivo. The tight control over BAFF expression plays an important role in enforcing self-tolerance, as is illustrated by the escape of some self-reactive B cell clones and the production of autoantibodies that accompanies the elevation of BAFF levels in vivo. Recent experiments have identified the molecular basis for the unique dependence of B cells on survival signals delivered by BAFF. In the absence of BAFF, B cell survival is constitutively suppressed through the cooperative actions of the TRAF2 and TRAF3 signal adapters. BAFF circumvents this activity by triggering the recruitment of TRAF3 to BAFF-R and causing the depletion of TRAF3 from the cell via a TRAF2-dependent mechanism. In this way, critical B cell survival signals such as the alternative NF-?B pathway are activated. Sustained exposure to BAFF is normally required to maintain the activity of these pathways and B cell survival. However, this requirement is completely removed in B cells that lack expression of TRAF2 or TRAF3.
|Authors||Gardam, S.; Brink, R.|
|Responsible Garvan Author|
|Publisher Name||Contemporary Immunology:BLys Ligands and Receptors|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10350|