In vivo studies of B cell differentiation during the extrafollicular and germinal centre responses to T- dependent antigens

Al-zahrani, Amani Taher (2026). In vivo studies of B cell differentiation during the extrafollicular and germinal centre responses to T- dependent antigens. University of Birmingham. Ph.D.

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Abstract

The connection between antibody affinity maturation and the quality of humoral immunity is critical for inducing a protective immune response. Considering that plasma cells (PCs) can be extrafollicular (EF) and germinal centre (GC)-dependent, the S1pr2\(^{CreERT2}\) Rosa26\(^{LSLtdTomato}\) Prdm1\(^{GFP}\) mouse model was used to distinguish EFderived and GC-derived PCs. Using this mouse model, early GC-derived plasmablasts (PBs) peaked at day 5, whereas GC-matured PCs accumulated by day 6. Furthermore, EF-derived Blimp-1\(^{GFP+}\) plasmablasts-plasma cells (PBs-PCs) were detected within the GC cluster, representing an unexpected observation, the basis of which remains to be determined.

In the IgMg1AID\(^{Cre}\) mouse model, expansion of IgG1\(^+\) GC B cells was confirmed to drive the reduction of IgM\(^+\) GC B cells in the original IgMg1 model. Interestingly, the chimeric IgG1 tail controlled Tfh cells and GC B cell expansion in the IgMg1AID\(^{Cre}\) mouse model, unlike the marked expansion of Tfh cells in the IgMg1 model and GC B cells in the AID\(^{Cre}\) model.

In the recall immune response, we investigated how the location and nature of the initial priming event shaped the B cell response after a boost with the same antigen. The recruitment of memory B cells at local versus distal sites determines the magnitude of the recall response. Distal sites can act as secondary survival niches for PBs-PCs, thereby supporting sustained antibody production. In addition, the abundance of NPbinding naive B cells at both sites may further influence the effectiveness of the recall response.

These in vivo models should be useful to interrogate the biology of B cell differentiation that allows us to investigate multiple stages simultaneously.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):