Resolve, revise, and relax: The 3 Rs of B cell repertoire adjustment

Competition for limited, cell extrinsic survival factors is a general feature of peripheral selection checkpoints involved in B lymphocyte maturation and activation. Perhaps the best-characterized example involves BLyS (B lymphocyte stimulator), which modulates the size and composition of mature naïve B cell pools, but evidence for analogous competitive checkpoints is emerging for both germinal center B cells and plasma cells. Here we discuss how deliberate alteration of BLyS levels might be used to manipulate B cell repertoire selection in order to restore self-tolerance in autoimmunity, remodel the repertoire to accommodate neo-self antigens introduced through transplantation and gene therapy, or expand repertoire diversity to reveal novel, therapeutically useful specificities.

► BLyS links B cell homeostasis with peripheral tolerance.
► Deliberate alteration of BLyS levels might allow repertoire manipulation.
► This approach could resolve aberrant selection after B cell depletion.
► An emerging idea is repertoire revision fostering tolerance to antigens introduced by transplant or gene therapy.
► Relaxing repertoire selection might reveal novel specificities useful in therapeutic or prophylactic vaccine development.