Competition for refueling rather than cyclic reentry initiation evident in germinal centers

Long Z, Phillips B, Radtke D, Meyer-Hermann M, Bannard O (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Science immunology American Association for the Advancement of Science

Book Volume: 7

Journal Issue: 69

DOI: 10.1126/sciimmunol.abm0775

Abstract

Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and proliferation in dark zones (DZs) and selection in light zones (LZs). GC B cells exit cell cycle a number of hours before entering LZs; therefore, continued participation in responses requires that they subsequently reenter cell cycle and move back to DZs, a process known as cyclic reentry. Affinity enhancements are thought to arise by B cells having to compete to initiate cyclic reentry each time they enter LZs, with T cell help being a major determinant; however, direct proof is lacking. Using Fucci2 mice, we confirmed an association between B cell receptor affinity and the first step of cyclic reentry, S phase initiation from a resting LZ state. However, neither T cell ablation nor MHCII deletion prevented resting LZ cells from reentering cell cycle, and this late G(1)-S transition was also not detectably restricted by competition. In contrast, using BATF induction as exemplar, we found that T cells "refueled" LZ cells in an affinity-dependent manner that was limited by both competition and cells' intrinsic antigen-acquiring abilities. Therefore, cyclic reentry initiation and B cell refueling are independently regulated in GCs, which may contribute to permitting cells of different competencies to be sustained alongside each other and allow T cell support to be provided across a dynamic range commensurate with affinity. We speculate that this less binary selection mechanism could help GCs nurture complex antibody maturation pathways and support the clonal diversity required for countering fast-evolving pathogens.

Involved external institutions

University of Oxford GB United Kingdom (GB) Helmholtz-Zentrum für Infektionsforschung (HZI) DE Germany (DE)

How to cite

APA:

Long, Z., Phillips, B., Radtke, D., Meyer-Hermann, M., & Bannard, O. (2022). Competition for refueling rather than cyclic reentry initiation evident in germinal centers. Science immunology, 7(69). https://dx.doi.org/10.1126/sciimmunol.abm0775

MLA:

Long, Ziqi, et al. "Competition for refueling rather than cyclic reentry initiation evident in germinal centers." Science immunology 7.69 (2022).

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