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.
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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.
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