The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis

To reconcile conflicting reports on the role of CD40 signaling in germinal center (GC) formation, we examined the earliest stages of murine GC B cell differentiation. Peri-follicular GC precursors first expressed intermediate levels of BCL6 while co-expressing the transcription factors RelB and IRF4, the latter known to repress Bcl6 transcription. Transition of GC precursors to the BCL6hi follicular state was associated with cell division, although the number of required cell divisions was immunogen dose dependent. Potentiating T cell help or CD40 signaling in these GC precursors actively repressed GC B cell maturation and diverted their fate towards plasmablast differentiation, whereas depletion of CD4+ T cells promoted this initial transition. Thus while CD40 signaling in B cells is necessary to generate the immediate precursors of GC B cells, transition to the BCL6hi follicular state is promoted by a regional and transient diminution of T cell help.

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The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help

Journal of Experimental Medicine ◽

10.1084/jem.20161263 ◽

2017 ◽

Vol 214 (4) ◽

pp. 1181-1198 ◽

Cited By ~ 40

Author(s):

Takeshi Inoue ◽

Ryo Shinnakasu ◽

Wataru Ise ◽

Chie Kawai ◽

Takeshi Egawa ◽

...

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

T Cell ◽

B Cells ◽

Germinal Center ◽

Dependent Manner ◽

Immunoglobulin Genes ◽

Functional Transition ◽

Germinal Center B Cell ◽

T Cell Help

Germinal center (GC) B cells cycle between two states, the light zone (LZ) and the dark zone (DZ), and in the latter they proliferate and hypermutate their immunoglobulin genes. How this functional transition takes place is still controversial. In this study, we demonstrate that ablation of Foxo1 after GC development led to the loss of the DZ GC B cells and disruption of the GC architecture, which is consistent with recent studies. Mechanistically, even upon provision of adequate T cell help, Foxo1-deficient GC B cells showed less proliferative expansion than controls. Moreover, we found that the transcription factor BATF was transiently induced in LZ GC B cells in a Foxo1-dependent manner and that deletion of BATF similarly led to GC disruption. Thus, our results are consistent with a model where the switch from the LZ to the DZ is triggered after receipt of T cell help, and suggest that Foxo1-mediated BATF up-regulation is at least partly involved in this switch.

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BCL6-Mediated Silencing of PD-1 Ligands in Germinal Center B Cells Maintains Follicular T Cell Population

The Journal of Immunology ◽

10.4049/jimmunol.1800876 ◽

2018 ◽

Vol 202 (3) ◽

pp. 704-713 ◽

Cited By ~ 8

Author(s):

Cheng Peng ◽

Qianwen Hu ◽

Fang Yang ◽

Heng Zhang ◽

Fubin Li ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Cell Population ◽

Germinal Center ◽

Germinal Center B Cells

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Ex vivo synthetic immune tissues with T cell signals for differentiating antigen-specific, high affinity germinal center B cells

Biomaterials ◽

10.1016/j.biomaterials.2018.06.034 ◽

2019 ◽

Vol 198 ◽

pp. 27-36 ◽

Cited By ~ 11

Author(s):

Alberto Purwada ◽

Shivem B. Shah ◽

Wendy Béguelin ◽

Avery August ◽

Ari M. Melnick ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Germinal Center ◽

Ex Vivo ◽

High Affinity ◽

Immune Tissues ◽

Germinal Center B Cells ◽

Cell Signals

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A dynamic T cell–limited checkpoint regulates affinity-dependent B cell entry into the germinal center

Journal of Experimental Medicine ◽

10.1084/jem.20102477 ◽

2011 ◽

Vol 208 (6) ◽

pp. 1243-1252 ◽

Cited By ~ 214

Author(s):

Tanja A. Schwickert ◽

Gabriel D. Victora ◽

David R. Fooksman ◽

Alice O. Kamphorst ◽

Monica R. Mugnier ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Cell Entry ◽

Multiphoton Imaging ◽

Histocompatibility Complex ◽

Cell Clones ◽

T Cell Help

The germinal center (GC) reaction is essential for the generation of the somatically hypermutated, high-affinity antibodies that mediate adaptive immunity. Entry into the GC is limited to a small number of B cell clones; however, the process by which this limited number of clones is selected is unclear. In this study, we demonstrate that low-affinity B cells intrinsically capable of seeding a GC reaction fail to expand and become activated in the presence of higher-affinity B cells even before GC coalescence. Live multiphoton imaging shows that selection is based on the amount of peptide–major histocompatibility complex (pMHC) presented to cognate T cells within clusters of responding B and T cells at the T–B border. We propose a model in which T cell help is restricted to the B cells with the highest amounts of pMHC, thus allowing for a dynamic affinity threshold to be imposed on antigen-binding B cells.

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

10.1101/061879 ◽

2016 ◽

Author(s):

Vinod Krishna ◽

Kurtis E. Bachman

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Peripheral Tolerance ◽

B Cell Tolerance ◽

Germinal Center Reaction ◽

Dark Zone ◽

T Cell Help ◽

Selection Of

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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B cell function in mice transgenic for mCTLA4-H gamma 1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.179.3.819 ◽

1994 ◽

Vol 179 (3) ◽

pp. 819-830 ◽

Cited By ~ 94

Author(s):

P Lane ◽

C Burdet ◽

S Hubele ◽

D Scheidegger ◽

U Müller ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Transgenic Mice ◽

B Cell ◽

Germinal Center ◽

Cd4 T Cells ◽

Class Switching ◽

T Cell Help ◽

Germinal Center Formation

This report outlines the B cell phenotype of transgenic mice that overexpresses the mouse CTLA-4-human gamma 1 (mCTLA4-H gamma 1) protein. Despite the fact that these mice prime CD4+ T cells (Ronchese, F., B. Housemann, S. Hubele, and P. Lane. 1994. J. Exp. Med. 179:809), antibody responses to T-dependent antigens are severely impaired. In contrast, T-independent responses are normal which suggests mCTLA4-H gamma 1 does not act directly on B cells, but acts indirectly by impairing T cell help. The impaired antibody defect is associated with impaired class switching, with low total immunoglobulin (Ig)G and antigen-specific IgG responses, and an absence of germinal center formation in spleen and lymph nodes but not gut-associated tissues. The defective germinal center formation is associated with a reduction in the degree of somatic mutation in hybridomas made from transgenic mice in comparison with those made from normal mice. It seems likely that mCTLA4-H gamma 1 exerts its effect by blocking an interaction between T and B cells that induce T cell help for B cells.

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

PLoS ONE ◽

10.1371/journal.pone.0200241 ◽

2018 ◽

Vol 13 (8) ◽

pp. e0200241 ◽

Cited By ~ 2

Author(s):

Vinod Krishna ◽

Kurtis E. Bachman

Keyword(s):

T Cell ◽

B Cells ◽

Germinal Center ◽

Selection Of ◽

Germinal Center B Cells

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Germinal Center Marker GL7 Probes Activation-Dependent Repression of N-Glycolylneuraminic Acid, a Sialic Acid Species Involved in the Negative Modulation of B-Cell Activation

Molecular and Cellular Biology ◽

10.1128/mcb.02047-06 ◽

2007 ◽

Vol 27 (8) ◽

pp. 3008-3022 ◽

Cited By ~ 120

Author(s):

Yuko Naito ◽

Hiromu Takematsu ◽

Susumu Koyama ◽

Shizu Miyake ◽

Harumi Yamamoto ◽

...

Keyword(s):

Sialic Acid ◽

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

Cell Activation ◽

Germinal Centers ◽

Negative Regulator ◽

B Cell Activation ◽

Germinal Center B Cells

ABSTRACT Sialic acid (Sia) is a family of acidic nine-carbon sugars that occupies the nonreducing terminus of glycan chains. Diversity of Sia is achieved by variation in the linkage to the underlying sugar and modification of the Sia molecule. Here we identified Sia-dependent epitope specificity for GL7, a rat monoclonal antibody, to probe germinal centers upon T cell-dependent immunity. GL7 recognizes sialylated glycan(s), the α2,6-linked N-acetylneuraminic acid (Neu5Ac) on a lactosamine glycan chain(s), in both Sia modification- and Sia linkage-dependent manners. In mouse germinal center B cells, the expression of the GL7 epitope was upregulated due to the in situ repression of CMP-Neu5Ac hydroxylase (Cmah), the enzyme responsible for Sia modification of Neu5Ac to Neu5Gc. Such Cmah repression caused activation-dependent dynamic reduction of CD22 ligand expression without losing α2,6-linked sialylation in germinal centers. The in vivo function of Cmah was analyzed using gene-disrupted mice. Phenotypic analyses showed that Neu5Gc glycan functions as a negative regulator for B-cell activation in assays of T-cell-independent immunization response and splenic B-cell proliferation. Thus, Neu5Gc is required for optimal negative regulation, and the reaction is specifically suppressed in activated B cells, i.e., germinal center B cells.

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