A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells

PLOS ONE, Aug 2018

A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the Germinal Center reaction. Finally, we demonstrate that clonal expansion upon return to the Germinal Center dark zone amplifies differences in the antigen affinity of B cells that survive the light zone.

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A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells

August A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells Vinod Krishna 0 1 Kurtis E. Bachman 0 1 0 Computational Biology, Discovery Sciences, Janssen Research and Development LLC. , 1400 McKean Road, Spring House, PA , United States of America 1 Editor: Stephen J Turner, Monash University , Australia , AUSTRALIA A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the Germinal Center reaction. Finally, we demonstrate that clonal expansion upon return to the Germinal Center dark zone amplifies differences in the antigen affinity of B cells that survive the light zone. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The funder provided support in the form of salaries for authors V.K and K.E.B, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the `author contributions' section. The ªinternal fundingº provided for this work was solely in the form of salaries paid to V.K and K.E.B by Janssen Research Introduction The ability of B cells to form antibodies against unknown foreign antigens is fundamental to immunity against infection. B cells are able to synthesize antibodies by undergoing an evolutionary process which involves the mutation and selection of their B cell receptors (BCRs) for enhanced antigen-specific recognition, resulting in affinity maturation of B cells. In the initial stage of early antigen engagement, B cells are enriched for those with receptors that have an adequate antigen binding affinity. The enriched B cell populations then migrate to specialized anatomical structures that form in the lymph nodes and similar organs, known as germinal centers (GC), where B cell receptor affinity maturation occurs. B cells in the GC undergo clonal expansion and somatic hypermutation (SHM) at the BCR. This is followed by antigen uptake by the hypermutated B cells from GC resident follicular dendritic cells (FDC's) and selection between the resulting antigen presenting hypermutated B cells for affinity maturation by follicular helper T cells (Tfh cells). [1] According to the classic model of GC B cell affinity maturation, GC B cell somatic hypermutation and clonal expansion occur in a spatially distinct GC ªdark zoneº (DZ), while antigen loading by follicular dendritic cells (FDC's) and B cell selection occur in the so-called GC ªlight zoneº (LZ) (Fig 1a). [1] While this model of B cell affinity maturation explains the broad contours of how immunological tolerance is maintained or re-established by the GC reaction, it is not clear how B cell interactions with antigen bound FDC's and Tfh cells in the GC result in both a positive selection for highly antigen specific BCRs, and a negative selection against self reactive B cells. and Development LLC, and the funders had no role in the choice of problem, study design, data collection, analysis and decision to publish or the preparation and revision of this manuscript. Experiments have shown that the affinity selection of B cells in the GC light zone is limited by access to costimulation by Tfh cells. [2±5] On the other hand, while somatic hypermutation and clonal expansion of B cells result in a few clones with improved antigen affinity, the majority of hypermutated B cells are likely to be either self reactive or have degraded affinity for antigen. [6±8] In addition, Tfh cells recognize short peptide antigen epitopes through T cell receptor (TCR) binding to pMHC complexes, while affinity maturation requires optimizing the binding affinity of the BCR to antigen epitopes which are often distinct from epitopes presented on MHC. A central question is to reconcile these observations and describe the mechanism that governs the selection of high affinity, antigen specific B cells out of the large pool of hypermutated B cells with low and intermediate affinity, while at the same time also eliminating hypermutated B cells with cross reactivity to both antigen and self proteins. Specifically, in this paper we address how B cells that enter the GC LZ could undergo both a positive selection for antigen binding affinity and a negative selection against autoreactive B cells through encounters with Tfh cells. In addition, we examine how selection of Tfh cell specific antigen epitopes could also result in selection for higher BCR antigen affinity. In this (...truncated)


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Vinod Krishna, Kurtis E. Bachman. A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells, PLOS ONE, 2018, Volume 13, Issue 8, DOI: 10.1371/journal.pone.0200241