Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen

Taylor, Justin J.; Martinez, Ryan; Titcombe, Philip J.; Barsness, Laura O.; Thomas, Stephanie R.; Zhang, Na; Katzman, Shoshana D.; Jenkins, Marc K.; Mueller, Daniel L.

doi:10.1084/jem.20112272

Cited by 137 publications

(206 citation statements)

References 33 publications

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“…Recent studies tracking autoreactive B-cell populations in the wild-type repertoire have argued that for some classes of self-antigens, B-cell tolerance is achieved not by deletion or anergy but largely through a lack of cognate T-cell help (40). Overall, these data support a model where thymic B cells couple a broad recognition of self-antigens with an enhanced antigen-presentation capacity to purge cognate T cells from the developing repertoire.…”

Section: Igmmentioning

confidence: 72%

Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection

Perera¹,

Meng²,

Meng

et al. 2013

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

157

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The thymus contains a population of B cells that colocalize with dendritic cells and medullary thymic epithelial cells in the thymic medulla. The development and functional significance of these cells are largely unknown. Using recombination-activating gene 2 GFP reporter mice along with parabiosis experiments, we demonstrate that the vast majority of thymic B cells develop from progenitors within the thymus. Thymic B cells express unique phenotypic markers compared with peripheral B cells; particularly they express high levels of MHC class II, suggesting that they are poised to present selfantigens efficiently. Using Ig knock-in and T-cell receptor transgenic mice specific for the self-antigen glucose-6-phosphate isomerase, we show that autoreactive thymic B cells serve as efficient antigen-presenting cells for T cell negative selection even when they are present at low frequencies. Furthermore, the endogenous thymic B-cell repertoire also functions in this capacity. These results suggest that developing thymic B cells could efficiently capture a broad array of autoantigens through their B-cell receptors, presenting peptides derived from those autoantigens to developing thymocytes and eliminating cognate T cells.N egative selection purges autoreactive T cells from the immune repertoire and is the major mechanism of central tolerance in the thymus. This process depends on presentation of self-peptides to developing thymocytes by antigen-presenting cells (APCs). The question of which APC presents self-antigen for negative selection has been investigated extensively. Initial studies using bone marrow chimeras found that bone-marrowderived hematopoietic cells are required for negative selection (reviewed in refs. 1 and 2). Many subsequent studies have demonstrated that cortical and medullary thymic epithelial cells (mTECs) can be quite efficient for negative selection as well (1-3). The role of mTECs in deleting T cells specific for tissue-restricted antigens has been highlighted by autoimmunity in both humans and mice possessing mutations in the AIRE gene, which controls the expression of tissue-specific self-antigens in mTECs (4).Bone-marrow-derived APCs include dendritic cells (DCs), B cells, and macrophages. In vitro assays comparing their relative antigen presentation efficiency showed that DCs were the most efficient, leading to the conclusion that DCs were largely responsible for negative selection in the thymus (5). Although B cells are poor at presenting antigens via nonspecific uptake, they capture and internalize cognate antigens that are bound by their B-cell receptors and present them very efficiently (6, 7). Therefore, antigen-specific B cells could be the most efficient APC on a per cell basis for a particular antigen.The thymus contains a small population of B cells that make up around 0.1-0.5% of thymocytes (8-12), similar to the proportion of DCs and mTECs in the thymus (13-15). The origin of thymic B cells has been debated, and development from intrathymic progenitors and migration from the perip...

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Section: Igmmentioning

confidence: 72%

Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection

Perera¹,

Meng²,

Meng

et al. 2013

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

157

View full text Add to dashboard Cite

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“…For antigen-specific B cell experiments, a 14-kDA truncated carboxy terminus of PyMSP1 was cloned, purified, biotinylated, and tetramerized with streptavidin-PE (Prozyme) as previously described (38,96). Decoy reagent to detect B cells specific for tetramer components was constructed as previously described (17,43).…”

Section: Methodsmentioning

confidence: 99%

“…Because cGAS has been reported to affect the T-independent B cell response (15), we hypothesized that the loss of parasite control we had observed in cGAS -/-mice could be associated with a loss of early plasmablast formation in a T cell-independent fashion. To examine the antigen-specific B cell response, we used a B cell tetramer comprising the C-terminal portion of the merozoite surface protein 1 (MSP1) protein of P. yoelii (17,38). Antibodies against MSP1 are associated with clinical immunity in endemic populations (39,40) and murine models of Plasmodium infection (41,42).…”

Section: Cd11bmentioning

confidence: 99%

“…This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16). B cell tetramers were additionally used to identify polyclonal P. yoelii-specific B cells (17). Using these tools, we demonstrated that cGAS deficiency had no effect on the early priming, differentiation, or expansion of Plasmodium-specific CD4 + T cells or B cells.…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Hahn¹,

Butler²,

Lindner³

et al. 2018

JCI Insight

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“…Pre-clinical and clinical studies of SUD vaccines showed that post-immunization anti-drug Ab levels and affinity vary greatly across subjects, but the cause of such variability is not clear. 10 Before and after immunization, the number of antigen-specific B and T cells in the total lymphocyte repertoire varies in individual mice 33,[36][37][38][39][52][53][54][55][56][57][58] and in human subjects. 59,60 Consistently, individual variability of similar magnitude has been found in the polyclonal hapten-specific B cell population in blood, peripheral lymph nodes and spleen of various mouse strains, before and after immunization with vaccines for oxycodone and nicotine.…”

Section: Pre-clinical Developmentmentioning

confidence: 99%

Biologics to treat substance use disorders: Current status and new directions

Pravetoni

2016

Human Vaccines & Immunotherapeutics

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Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen

Abstract: Both deletion and anergy shape B cell tolerance to membrane-bound antigens.

Cited by 137 publications

References 33 publications

Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection

Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Biologics to treat substance use disorders: Current status and new directions

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