Re-evaluating the basis of clonal selection in germinal centres
Effective humoral responses rely on the development of high-affinity antigen-specific B cells. However, the naïve repertoire of antibodies usually shows low affinity. B cells need to improve their affinity in secondary lymphoid structures known as germinal centres (GCs) during infections, a process...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2022
|
| Subjects: |
| _version_ | 1797109951960711168 |
|---|---|
| author | Long, Z |
| author2 | Bannard, O |
| author_facet | Bannard, O Long, Z |
| author_sort | Long, Z |
| collection | OXFORD |
| description | Effective humoral responses rely on the development of high-affinity antigen-specific B cells. However, the naïve repertoire of antibodies usually shows low affinity. B cells need to improve their affinity in secondary lymphoid structures known as germinal centres (GCs) during infections, a process known as affinity maturation. In GCs, B cells undergo iterative rounds of somatic hypermutation in the dark zones (DZs) to diversify BCRs then exit cell cycle and move back to light
zones (LZs) for affinity-based selection. In the LZs, it has long been considered that only selected cells could subsequently reenter cell cycle and move back to DZs, a process known as cyclic re-entry. Affinity enhancements are thought to be conferred via T cells providing help to the highest affinity LZ B cells to initiate cyclic re-entry, however, this hypothesis was never directly tested. Using fluorescent cell cycle
reporter mice, we found neither T cells depletion nor MHCII deletion abolished the cyclic re-entry initiation in LZ cells and this process was not detectably restricted by general intra-GC competition. Concurrently, using BATF as a marker for recent T-B interactions, we found B cells needed to compete in order to receive T cell mediated refuelling in an affinity dependent manner. However, this process was also limited
by B cells’ intrinsic ability to acquire antigens. Consistent with the observations above, cyclic re-entry LZ cells were found to be heterogeneous at their BATF levels, further confirming cyclic re-entry initiation and receiving T cell mediated refuelling are two processes regulated independently. Our data is pointing towards a less
binary selection mechanism in GCs, which confers proliferative advantage to higher affinity clones while allowing low-affinity cells to mature via more complex pathways so that antibody repertoires are matured for both affinity and clonal diversity.
|
| first_indexed | 2024-03-07T07:48:23Z |
| format | Thesis |
| id | oxford-uuid:600aacb9-45d7-476d-a32d-5da842853582 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:48:23Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:600aacb9-45d7-476d-a32d-5da8428535822023-06-27T15:14:38ZRe-evaluating the basis of clonal selection in germinal centresThesishttp://purl.org/coar/resource_type/c_db06uuid:600aacb9-45d7-476d-a32d-5da842853582ImmunologyEnglishHyrax Deposit2022Long, ZBannard, OEffective humoral responses rely on the development of high-affinity antigen-specific B cells. However, the naïve repertoire of antibodies usually shows low affinity. B cells need to improve their affinity in secondary lymphoid structures known as germinal centres (GCs) during infections, a process known as affinity maturation. In GCs, B cells undergo iterative rounds of somatic hypermutation in the dark zones (DZs) to diversify BCRs then exit cell cycle and move back to light zones (LZs) for affinity-based selection. In the LZs, it has long been considered that only selected cells could subsequently reenter cell cycle and move back to DZs, a process known as cyclic re-entry. Affinity enhancements are thought to be conferred via T cells providing help to the highest affinity LZ B cells to initiate cyclic re-entry, however, this hypothesis was never directly tested. Using fluorescent cell cycle reporter mice, we found neither T cells depletion nor MHCII deletion abolished the cyclic re-entry initiation in LZ cells and this process was not detectably restricted by general intra-GC competition. Concurrently, using BATF as a marker for recent T-B interactions, we found B cells needed to compete in order to receive T cell mediated refuelling in an affinity dependent manner. However, this process was also limited by B cells’ intrinsic ability to acquire antigens. Consistent with the observations above, cyclic re-entry LZ cells were found to be heterogeneous at their BATF levels, further confirming cyclic re-entry initiation and receiving T cell mediated refuelling are two processes regulated independently. Our data is pointing towards a less binary selection mechanism in GCs, which confers proliferative advantage to higher affinity clones while allowing low-affinity cells to mature via more complex pathways so that antibody repertoires are matured for both affinity and clonal diversity. |
| spellingShingle | Immunology Long, Z Re-evaluating the basis of clonal selection in germinal centres |
| title | Re-evaluating the basis of clonal selection in germinal centres |
| title_full | Re-evaluating the basis of clonal selection in germinal centres |
| title_fullStr | Re-evaluating the basis of clonal selection in germinal centres |
| title_full_unstemmed | Re-evaluating the basis of clonal selection in germinal centres |
| title_short | Re-evaluating the basis of clonal selection in germinal centres |
| title_sort | re evaluating the basis of clonal selection in germinal centres |
| topic | Immunology |
| work_keys_str_mv | AT longz reevaluatingthebasisofclonalselectioningerminalcentres |