|M.Sc Student||Ammouri Manal|
|Subject||IgG1 B Cell Receptor Promotes Development of B Cells in|
the Bone Marrow and Confers Extended Survival in
|Department||Department of Medicine||Supervisor||Professor Doron Melamed|
|Full Thesis text|
Development of B-lineage cells is characterized by progression through a series of checkpoints defined primarily by rearrangement and expression of immunoglobulin heavy and light chain. Upon appropriate stimulation, mature B cells can undergo class-switch recombination (CSR). At the termination of the response, memory B cells are generated. Memory B cells are long-lived and mount robust responsiveness upon secondary challenges. Currently, the mechanism for the increased responsiveness of memory B cells relative to naïve B cells is unclear.
In a normal mouse, CSR is linked with cell activation and differentiation, thereby limiting the ability to address these questions. To enable assessing a single event in the pathway of Memory B cell generation, we used a novel mouse model in which B cell development relies either on the expression of membrane-bound γ1 (IgGi mice) or µ (IgMi mice) heavy chains. Our study aimed to determine whether IgG receptors can promote B lymphopoiesis and to study whether the CSR by itself is sufficient to confer memory characteristics.
We found that IgG1 driven development in the bone marrow is compromised with a partial block at the pro-to-pre B cell transition. By breading to a mouse model that allows switching from IgM to IgG in early progenitors (CD19-Cre), we demonstrate that the block is circumvented by switching to Cµ.
We demonstrate that Cγ1 expressing cells mature to the periphery and are dependent on BAFF (B cell Activating Factor) signaling for survival.
We also found significantly higher basal “tonic” phosphorylation levels in splenic Cγ1 expressing cells.
By analysing the light chain repertoire in IgMi and IgGi mice we demonstrate that the Cγ1 expressing cells have higher frequency of lambda light chain utilization compared to Cµ and bias patterns of V-kappa light chain utilization which could be based on structural similarity. This suggests that Cγ1 expressing cells undergo light chain selection process differently than Cµ expressing cells.
Finally, by using an inducible mouse model which allows Cre induced switching from IgM to IgG1 expression without undergoing BCR activation and differentiation processes, we demonstrate that cells undergone switching to IgG1 become long lived and have longer life span than the IgM expressing cells.
In summary, Cγ1 heavy chain supports development of B cells in the BM with a partial block in the pro to pre B differentiation step, while in the periphery mature B cells expressing the Cγ1 heavy chain have extended survival over Cµ expressing cells.