Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging.
Immunity
; 49(3): 477-489.e7, 2018 09 18.
Article
in En
| MEDLINE
| ID: mdl-30231983
ABSTRACT
Adaptive immunity involves the development of bespoke antibodies in germinal centers (GCs) through immunoglobulin somatic hypermutation (SHM) in GC dark zones (DZs) and clonal selection in light zones (LZs). Accurate selection requires that cells fully replace surface B cell receptors (BCRs) following SHM, but whether this happens before LZ entry is not clear. We found that most GC B cells degrade pre-SHM receptors before leaving the DZ, and that B cells acquiring crippling mutations during SHM rarely reached the LZ. Instead, apoptosis was triggered preferentially in late G1, a stage wherein cells with functional BCRs re-entered cell cycle or reduced surface expression of the chemokine receptor CXCR4 to enable LZ migration. Ectopic expression of the anti-apoptotic gene Bcl2 was not sufficient for cells with damaging mutations to reach the LZ, suggesting that BCR-dependent cues may actively facilitate the transition. Thus, BCR replacement and pre-screening in DZs prevents the accumulation of clones with non-functional receptors and facilitates selection in the LZ.
Full text:
1
Collection:
01-internacional
Health context:
4_TD
Database:
MEDLINE
Main subject:
Immunoglobulins
/
B-Lymphocytes
/
Receptors, Antigen, B-Cell
/
Germinal Center
/
Clonal Selection, Antigen-Mediated
Limits:
Animals
Language:
En
Journal:
Immunity
Year:
2018
Document type:
Article