Decision events in the germinal centre: the role of ACKR4

Murine atypical chemokine receptor 4, ACKR4, which binds to chemokines CCL19, CCL21 and CCL25, is expressed specifically in germinal centre (GC) B cells and in a layer of stromal cells surrounding the splenic marginal zone. Although ACKR4 is unable to signal as classical GPCRs, it creates gradients of its ligands. It is shown here that ACKR4 deficiency in the stroma causes infiltration of naive B cells into the GC area. ACKR4 deficiency in the B cells causes dysregulation of the intragerminal centre distribution, with enlarged light zones and reduced dark zones when compared to ACKR4-competent mice. This skewed GC distribution is caused by the inability of ACKR4-deficient B cells to downregulate c-Myc, as they receive increased signalling though the CCR7- p-Akt - c-Myc signalling pathway. Moreover, ACKR4-deficient mice contain elevated numbers of memory B cells (MBC) in the distant lymphoid organs. MBCs are retained in the draining lymph node (drLN) by the presence of a CCL19/21 gradient towards the subcapsular sinus (SCS). When this gradient is absent, as occurs in ACKR4-deficient mice, MBCs escape the drLN easier through the SCS and appear in other sites in elevated numbers. Together, this shows a new role for ACKR4 in the GC response and in the migration of GC-derived MBCs out of the follicle and the drLN.