Initial Clonal Expansion of Germinal Center B Cells Takes Place at the Perimeter of Follicles

Coffey, Francis; Alabyev, Boris Y.; Manser, Tim

doi:10.1016/j.immuni.2009.01.011

Cited by 108 publications

(111 citation statements)

References 48 publications

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“…1E). This pattern of follicular proliferation of early TD B cell blasts before GC formation was also identified in a recently published study (18).…”

Section: Early B Cell Proliferation Within the Primary B Cell Folliclesupporting

confidence: 80%

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Antigen Affinity Controls Rapid T-Dependent Antibody Production by Driving the Expansion Rather than the Differentiation or Extrafollicular Migration of Early Plasmablasts

Chan

Gatto²,

Wood³

et al. 2009

The Journal of Immunology

207

222

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To optimize the initial wave of Ab production against T-dependent Ags, primary B cell clones with the highest Ag affinity are selected to generate the largest extrafollicular plasmablast (PB) responses. The mechanism behind this remains undefined, primarily due to the difficulty of analyzing low frequency Ag-specific B cells during the earliest phases of the immune response when key differentiation decisions are made. In this study, a high resolution in vivo mouse model was used to characterize in detail the first 6 days of a T-dependent B cell response and to identify the steps at which initial Ag affinity has a major impact. Ag-specific B cells proliferated within splenic follicles from days 1.0 to 3.0 before undergoing a dynamic phase of multilineage differentiation (days 3.0–4.0) that generated switched and unswitched populations of germinal center B cells, early memory B cells, and extrafollicular PBs. PB differentiation was marked by synchronous up-regulation of CXCR4 and down-regulation of CXCR5 and the adoption of a unique BCRhigh phenotype by unswitched PBs. Differences in Ag affinity of >50-fold did not markedly affect the early stages of the response, including the differentiation and extrafollicular migration of PBs. However, high affinity PBs underwent significantly greater expansion within the splenic bridging channels and red pulp, due to both increased proliferation and decreased apoptosis. Extrafollicular PBs maintained class II MHC, but not IL-21R expression, and interacted directly with Ag-specific extrafollicular Th cells, suggesting that IL-21-independent T cell help may drive extrafollicular PB expansion in responses to foreign Ag.

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“…1E). This pattern of follicular proliferation of early TD B cell blasts before GC formation was also identified in a recently published study (18).…”

Section: Early B Cell Proliferation Within the Primary B Cell Folliclesupporting

confidence: 80%

“…1 and 2A) (1), the subsequent follicular migration and pre-GC Ig class switching by undifferentiated B cell blasts (Figs. 1 and 3C) (9,10,18), the generation of early memory B cells (Fig. 4B) (7), and the CXCR4 high , CXCR5…”

Section: Discussionmentioning

confidence: 92%

Antigen Affinity Controls Rapid T-Dependent Antibody Production by Driving the Expansion Rather than the Differentiation or Extrafollicular Migration of Early Plasmablasts

Chan

Gatto²,

Wood³

et al. 2009

The Journal of Immunology

207

222

View full text Add to dashboard Cite

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“…Localization within the T cell zone would allow CD8 + DCs to readily prime naive CD4 + T cells without requiring movement. In addition, it has been reported that Ag-specific B cells undergo clonal expansion in the outer follicle adjacent to the MZ before forming GCs in some circumstances (57,58). Thus, CD8a…”

Section: Cd8mentioning

confidence: 99%

Targeting Antigen to Clec9A Primes Follicular Th Cell Memory Responses Capable of Robust Recall

Kato

Zaid

Davey

et al. 2015

The Journal of Immunology

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Targeting Ags to dendritic cell (DC) surface receptors can induce a variety of responses depending on the DC type targeted, the receptor targeted, and the adjuvant used. Clec9A (DNGR-1), which is expressed by CD8+ DCs, has been shown to bind F-actin exposed on damaged cells. Targeting Ag to this receptor in mice and nonhuman primates induces strong humoral immunity even in the absence of adjuvant, a process seen for a few select DC receptors. In contrast with other receptors, however, targeting Clec9A induces long-lived, affinity-matured Ab responses that are associated with efficient CD4+ T cell responses shown to possess properties of follicular Th cells (TFH). In this article, we provide definitive evidence that Clec9A targeting promotes the development of TFH by showing that responding CD4 T cells express CXCR5, PD1, the TFH transcription factor Bcl6, and the cytokine IL-21, and that these cells localize to germinal centers. Furthermore, we extend studies from the model Ag OVA to the viral Ag glycoprotein D of HSV-1 and examine the capacity of primed TFH to form functional memory. We show that targeting glycoprotein D to Clec9A even in the absence of adjuvant induced long-lived memory CXCR5+ PD1hi CD4+ T cells that proliferated extensively upon secondary challenge and rapidly developed into effector TFH. This was associated with enhanced germinal center B cell responses and accelerated Ab production. Our study indicates that targeting Ags to Clec9A in the absence of adjuvant routinely generates TFH responses that form long-lived memory capable of robust secondary TFH responses.

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“…In contrast, in unimmunized recipients, B1-8 B cells and B1-8. H2-O −/− cells were present at similar percentages and ratios among the transferred NP-specific B cells ( (20). Therefore, expansion of the polyclonal T FH population by preimmunization should eliminate B1-8 B-cell competition for T-cell help and entry into GCs.…”

Section: Np-specific H2-o −/− B Cells Preferentially Populate the Gc mentioning

confidence: 99%

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

Draghi¹,

Denzin

2010

Proc. Natl. Acad. Sci. U.S.A.

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Upon antigen (Ag) encounter, B cells require T-cell help to enter the germinal center (GC). They obtain this help by presenting Agderived peptides on MHC class II (MHCII) for recognition by the T-cell receptor (TCR) of CD4 + T cells. Peptides are loaded onto MHCII in endosomal compartments in a process catalyzed by the MHCII-like protein H2-M (HLA-DM in humans). This process is modulated by another MHCII-like protein, H2-O (HLA-DO in humans). H2-O is a biochemical inhibitor of peptide loading onto MHCII; however, on the cellular level, it has been shown to have varying effects on Ag presentation. Thus, the function of H2-O in the adaptive immune response remains unclear. Here, we examine the effect of H2-O expression on the ability of Ag-specific B cells to enter the GC. We show that when Ag specific WT and H2-O −/− B cells are placed in direct competition, H2-O −/− B cells preferentially populate the GC. This advantage is confined to Ag-specific B cells and is due to their superior ability to obtain Ag-specific T-cell help when T-cell help is limiting. Overall, our work shows that H2-O expression reduces the ability of B cells to gain T-cell help and participate in the GC reaction.antigen processing | antigen presentation | H2-M | follicular helper T cells | HLA-DOA ntigen (Ag) processing and presentation on MHCII is central to T cell-dependent Ab-mediated immunity. During an immune response, Ag-specific naïve B cells recognize and internalize Ag via the B-cell receptor (BCR). The Ag is subsequently transported to late endosomes and lysosomes, where it is degraded into peptides, some of which are loaded onto MHC class II (MHCII) (1). These MHCII-peptide complexes are then displayed on the cell surface for recognition by cognate CD4 + T cells. This recognition event allows B cells to obtain T-cell help from a rare population of T cells known as CD4 + follicular helper T cells (T FH ). The interaction between the Ag-specific B cells and T FH cells is essential for B-cell entry into the germinal center (GC) (2).Peptide loading of MHCII is catalyzed by the nonclassical MHCII-like protein H2-M (HLA-DM in humans) (3-5). H2-M, which localizes to endosomes (6), promotes the removal of class IIassociated invariant chain peptides (CLIP) from the peptidebinding groove of MHCII. H2-M also stabilizes empty MHCII molecules and edits the final MHCII-bound peptide repertoire that is displayed at the cell surface to ensure that only long-lived MHCII-peptide complexes are presented (7). Another nonclassical MHCII-like protein, H2-O (HLA-DO in humans), also localizes to endosomes in B cells (8). H2-O forms a complex with H2-M and has been shown to inhibit or modulate the ability of H2-M to catalyze and edit MHCII peptide exchange (9-12). Surprisingly, H2-O-deficient mice exhibit only minor abnormalities in Ag presentation (11, 13).Ag presentation is important for many aspects of immunity, including initiating the GC response. Admission of B cells into the GC is a competitive process that is dependent upon help from Agspecific T F...

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Initial Clonal Expansion of Germinal Center B Cells Takes Place at the Perimeter of Follicles

Cited by 108 publications

References 48 publications

Antigen Affinity Controls Rapid T-Dependent Antibody Production by Driving the Expansion Rather than the Differentiation or Extrafollicular Migration of Early Plasmablasts

Antigen Affinity Controls Rapid T-Dependent Antibody Production by Driving the Expansion Rather than the Differentiation or Extrafollicular Migration of Early Plasmablasts

Targeting Antigen to Clec9A Primes Follicular Th Cell Memory Responses Capable of Robust Recall

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

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