Generation of emigrating memory B cells and their migratory behaviours

Burnett, Cameron Joseph Madoc (2024). Generation of emigrating memory B cells and their migratory behaviours. University of Birmingham. Ph.D.

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Abstract

The germinal centre (GC) reaction is a site of extensive B cell proliferation and somatic hypermutation of Ig variable region genes. Its outputs are plasma cells (PCs), selected from high affinity B cells, and memory B cells (mBCs), which are less stringently selected for affinity. Movements of lymphocytes within secondary lymphoid organs are dependent on an array of chemotactic cues. These play a role in lymphocyte entry, activation, and egress from the tissue.

A group of memory-like B cells migrating from GCs (BEMs) and entering the lymph node subcapsular sinus (SCS) were discovered in reactive lymph nodes (LNs). Some of these recycled between the SCS and back into the B cell follicles. S1PR1-blockade prevented migration of BEMs into the SCS, and deletion of ACKR4 prevented CCR7-ligand dependent recycling of BEMs back into the follicle. RNA-sequencing showed that BEMs shared some phenotypical characteristics with GC B cells but were a distinct subset of B cells. Cell surface markers were uncovered from RNA-sequencing to distinguish BEMs from GC B cells and naïve B cells at the peak of the GC response in the LN and spleen. ACKR4-mediated recycling of BEMs supported humoral responses to antigenic variants of chemical haptens as well as dengue virus envelope proteins.

Entry of circulating mBCs (BCMs) to distant lymphoid tissues was affected by CCR7 ligands. CCL21 was important for entry into non-reactive LNs and CCL19 may be directing entry into the spleen. ACKR4-deficient BCMs showed improved entry into distant lymphoid tissues, whereas CCR7-deficiency tended towards reduced entry.

Re-challenge experiments showed that mBCs were pre-disposed to a PC fate when re-exposed to antigen in an antigen-experienced LN. Conversely, BCMs in distant LNs that had no direct contact with antigen preferred GC B cell fates.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):