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Decision events in the germinal centre: the role of ACKR4

Garcia Ibanez, Laura (2017)
Ph.D. thesis, University of Birmingham.

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Abstract

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 naïve 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.

Type of Work:Ph.D. thesis.
Supervisor(s):Brown, Geoffrey and Toellner, K. M.
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute of Clinical Sciences
Subjects:QH301 Biology
QH426 Genetics
Institution:University of Birmingham
ID Code:7365
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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