Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation

Silver, Jared; Zuo, Teng; Chaudhary, Neha; Kumari, Richa; Tong, Pei; Giguere, Sophie; Granato, Alessandra; Donthula, Rakesh; Devereaux, Colby; Wesemann, Duane R.

doi:10.1084/jem.20171022

Cited by 33 publications

(29 citation statements)

References 36 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, acquisition of T cell help is sufficient to induce GC B cell expansion and PB formation, even in the absence of BCR engagement with Ag. These findings are consistent with a recent study that showed that, in the presence of abundant T cell help, non-Ag-specific B cells could participate in GCs and persist long enough to acquire specificity to Ag (Silver et al, 2018). Although loading GC B cells with T cell Ag peptides was sufficient to promote their selection and PB differentiation in a dose-dependent fashion (Figures 1L–1N; Gitlin et al, 2014), we found that Ag-dependent BCR engagement potentiated GC B cell expansion and PB differentiation when the amount of T cell Ag peptide loaded was subsaturating.…”

Section: Resultssupporting

confidence: 93%

B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting

Turner

Grigorova

2018

Cell Reports

View full text Add to dashboard Cite

SUMMARY Antigen-dependent engagement of germinal center (GC) B cell receptors (BCRs) promotes antigen internalization and presentation for follicular helper T cells. However, whether BCR signaling is critical or synergistic with T cell help for GC B cell selection or differentiation is unclear. Here, by adapting an experimental approach that enables independent delivery of BCR-crosslinking antigen or T cell help to GC B cells in vivo, we showed that T cell help was sufficient to induce GC B cell expansion and plasmablast formation. However, although BCR crosslinking could not by itself promote GC B cell selection or differentiation, it could synergize with T cell help to enhance the GC and plasmablast responses when T cell help was limiting. These findings indicate that GC B cells can integrate variable inputs from T cell help and BCR signaling in vivo for an optimal process of selection and differentiation, critical for potent long-term humoral immunity.

show abstract

Section: Resultssupporting

confidence: 93%

B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting

Turner

Grigorova

2018

Cell Reports

View full text Add to dashboard Cite

show abstract

“…low DND). This is consistent with data showing low affinity survivors in GCs (Kuraoka et al, 2016) or the persistence of unrelated BCs in the GC reaction (Silver et al, 2018). More generally speaking, GCs in the DisseD-theory are more permissive than in the other theories.…”

Section: Discussionsupporting

confidence: 90%

“…One might consider this experimental system artificial and non-physiological. However, a realistic theory of BC selection has to properly describe GCs permissive of low affinity BCs (Kuraoka et al, 2016;Silver et al, 2018) still allowing for efficient affinity maturation, diversity of GC clonal dominance (Tas et al, 2016) still allowing for clonal bursts, Tfh signal-dependent DND upon selection without losing the relevance of BCR signaling for selection, and also reflect extreme stimulation settings like antigen-uptake via the DEC205-receptor . A consistent theory, explaining these seemingly conflicting GC properties does not exist (Oprea & Perelson, 1997;Zhang & Shakhnovich, 2010;Meyer-Hermann et al, 2012;Wang et al, 2016;de Boer & Perelson, 2017;Meyer-Hermann, 2019).…”

Section: Introductionmentioning

confidence: 99%

Germinal center B cells separate signals for selection and division like compact discs

Meyer‐Hermann

2020

Preprint

View full text Add to dashboard Cite

Selection of B cells in germinal center (GC) reactions is pivotal to the generation of high affinity antibodies and memory B cells. Knowledge about B cell selection is limited to individual interactions and lacks global understanding. Here, seemingly contradictory experiments are unified in a common concept by separation of signals for the frequency of fate decision from the strength of cell division, which can then be controlled independently, similar to the separation of frequency and amplitude in digital audio signals. Based on this concept of information processing, three theories of B cell selection are developed that can be distinguish by predicted experiments drawn from computer simulations. Understanding encoding of information in molecular states is critical for targeted immune interventions.

show abstract

“…The TD-3 response is less likely to occur between resting B and T cells, but occurs between activated B and T cells upon infection or other pathogenic stimuli. The non-cognate or bystander interaction between T and B cells is important for the overall Ab responses as previously reported ( 57 66 67 68 ). Another example of non-cognate B cell help via MHC class II is when CD4 + T cell recognizes idiotypic peptides from immunoglobulin heavy chain variable domain present within the MHC class II molecule ( 64 ).…”

Section: Suggestion Of a New Sub-classification Of Td Ab Responsessupporting

confidence: 61%

Expansion and Sub-Classification of T Cell-Dependent Antibody Responses to Encompass the Role of Innate-Like T Cells in Antibody Responses

Park

Kim

2018

Immune Netw

View full text Add to dashboard Cite

In addition to T cell-dependent (TD) Ab responses, T cells can also regulate T cell-independent (TI) B cell responses in the absence of a specific major histocompatibility complex (MHC) class II and antigenic peptide-based interaction between T and B cells. The elucidation of T cells capable of supporting TI Ab responses is important for understanding the cellular mechanism of different types of TI Ab responses. Natural killer T (NKT) cells represent 1 type of helper T cells involved in TI Ab responses and more candidate helper T cells responsible for TI Ab responses may also include γδ T cells and recently reported B-1 helper CD4+ T cells. Marginal zone (MZ) B and B-1 cells, 2 major innate-like B cell subsets considered to function independently of T cells, interact with innate-like T cells. Whereas MZ B and NKT cells interact mutually for a rapid response to blood-borne infection, peritoneal memory phenotype CD49dhighCD4+ T cells support natural Ab secretion by B-1 cells. Here the role of innate-like T cells in the so-called TI Ab response is discussed. To accommodate the involvement of T cells in the TI Ab responses, we suggest an expanded classification of TD Ab responses that incorporate cognate and non-cognate B cell help by innate-like T cells.

show abstract

Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation

Abstract: Whether Ig engagement by antigen is required to initiate somatic evolution and affinity maturation is not well defined. Silver and colleagues show that germinal center flexibility permits nonspecific B cells to achieve de novo antigen recognition and antibody affinity maturation.

Cited by 33 publications

References 36 publications

B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting

B Cell Receptor Crosslinking Augments Germinal Center B Cell Selection when T Cell Help Is Limiting

Germinal center B cells separate signals for selection and division like compact discs

Expansion and Sub-Classification of T Cell-Dependent Antibody Responses to Encompass the Role of Innate-Like T Cells in Antibody Responses

Contact Info

Product

Resources

About