Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells

Avalos, Ana M.; Bilate, Angelina M.; Witte, Martin D.; Tai, Albert; He, Jiang; Frushicheva, Maria P.; Thill, Peter Daniel; Meyer‐Wentrup, Friederike; Theile, Christopher S.; Chakraborty, Arup K.; Zhuang, Xiaowei; Ploegh, Hidde L.

doi:10.1084/jem.20131603

Cited by 58 publications

(51 citation statements)

References 45 publications

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“…Moreover, both our studies and those of others showed that these accumulation events are sensitive to the biochemical and biophysical features of the antigens that B cells likely encounter in vivo (4,5). These features include but are not limited to antigen density (6,7), antigen affinity (6,7), antigen valency (8)(9)(10)(11)(12)(13), the mobility of the antigen (14)(15)(16)(17), the stiffness of the substrates presenting the antigen (18,19) and the mechanical forces delivered to the BCRs by the antigens (20,21). These facts highlight a long-standing question in immunology: how can the initiation of B-cell activation process the information of antigen specificity, density, affinity, valency, mobility, substrate stiffness, and mechanical forces in such an efficient way?…”

supporting

confidence: 62%

Utilization of a photoactivatable antigen system to examine B-cell probing termination and the B-cell receptor sorting mechanisms during B-cell activation

Wang

Tang

Wan

et al. 2016

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

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Antigen binding to the B-cell receptor (BCR) induces several responses, resulting in B-cell activation, proliferation, and differentiation. However, it has been difficult to study these responses due to their dynamic, fast, and transient nature. Here, we attempted to solve this problem by developing a controllable trigger point for BCR and antigen recognition through the construction of a photoactivatable antigen, caged 4-hydroxy-3-nitrophenyl acetyl (caged-NP). This photoactivatable antigen system in combination with live cell and single molecule imaging techniques enabled us to illuminate the previously unidentified B-cell probing termination behaviors and the precise BCR sorting mechanisms during B-cell activation. B cells in contact with caged-NP exhibited probing behaviors as defined by the unceasing extension of membrane pseudopods in random directions. Further analyses showed that such probing behaviors are cell intrinsic with strict dependence on F-actin remodeling but not on tonic BCR signaling. B-cell probing behaviors were terminated within 4 s after photoactivation, suggesting that this response was sensitive and specific to BCR engagement. The termination of B-cell probing was concomitant with the accumulation response of the BCRs into the BCR microclusters. We also determined the Brownian diffusion coefficient of BCRs from the same B cells before and after BCR engagement. The analysis of temporally segregated single molecule images of both BCR and major histocompatibility complex class I (MHC-I) demonstrated that antigen binding induced trapping of BCRs into the BCR microclusters is a fundamental mechanism for B cells to acquire antigens.he immune system uses immune receptors to sense and acquire antigens. Antigen binding induces a series of dynamic changes in the biophysical behaviors and biochemical features of the immune receptors, and these changes determine the fate of a cell (1-3). However, it has been difficult to accurately capture and thus comprehensively investigate these changes because they usually occur very quickly after immune recognition (1, 4). For example, recent live cell imaging studies showed that the B lymphocytes swiftly accumulate the surface-expressed B-cell receptors (BCRs) into the contact interface between the B cells and the antigen-presenting substrates to form a specialized membrane structure, the B-cell immunological synapse (IS) (1, 4). Moreover, both our studies and those of others showed that these accumulation events are sensitive to the biochemical and biophysical features of the antigens that B cells likely encounter in vivo (4, 5). These features include but are not limited to antigen density (6, 7), antigen affinity (6, 7), antigen valency (8-13), the mobility of the antigen (14-17), the stiffness of the substrates presenting the antigen (18, 19) and the mechanical forces delivered to the BCRs by the antigens (20, 21). These facts highlight a long-standing question in immunology: how can the initiation of B-cell activation process the information of antigen s...

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supporting

confidence: 62%

Utilization of a photoactivatable antigen system to examine B-cell probing termination and the B-cell receptor sorting mechanisms during B-cell activation

Wang

Tang

Wan

et al. 2016

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

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“…We expect that the coming years with further improved imaging approaches and novel structural studies will find ways to settle the controversies between these two seemingly contradictory models. Indeed, a recent study elegantly used defined ovalbumin peptides together with OB1 ovalbumin-specific BCR transgenic cells to show that also monomeric soluble antigens, when engaging the antigen-binding site, on the contrary to the constant region, of the BCR, are able to trigger signaling (36). This suggests that the antigen-binding site on the BCR may sculpt the signaling outcome and explain some of the discrepancies between various models.…”

Section: Initiation Of Bcr Signalingmentioning

confidence: 99%

Molecular Control of B Cell Activation and Immunological Synapse Formation

Kuokkanen

Šuštar

Mattila

2015

Traffic

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“…Alternatively, mis-folding simply might alter peptide-protein interactions and help in the development of larger antigen complexes providing a stronger stimulatory signal. Finally, a recent study with ovalbumin-peptide specific B cells indicated that although monomers can be recognized, dimers and multimers of a minimal peptide epitope are capable of eliciting stronger and qualitatively different cellular responses [66]. …”

Section: Discussionmentioning

confidence: 99%

γδ T cells recognize the insulin B:9–23 peptide antigen when it is dimerized through thiol oxidation

Aydintug

Zhang

Wang

et al. 2014

Molecular Immunology

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The insulin peptide B:9-23 is a natural antigen in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). In addition to αβ T cells and B cells, γδ T cells recognize the peptide and infiltrate the pancreatic islets where the peptide is produced within β cells. The peptide contains a cysteine in position 19 (Cys19), which is required for the γδ but not the αβ T cell response, and a tyrosine in position 16 (Tyr16), which is required for both. A peptide-specific mAb, tested along with the T cells, required neither of the two amino acids to bind the B:9-23 peptide. We found that γδ T cells require Cys19 because they recognize the peptide antigen in an oxidized state, in which the Cys19 thiols of two peptide molecules form a disulfide bond, creating a soluble homo-dimer. In contrast, αβ T cells recognize the peptide antigen as a reduced monomer, in complex with the MHCII molecule I-Ag7. Unlike the unstructured monomeric B:9-23 peptide, the γδ-stimulatory homo-dimer adopts a distinct secondary structure in solution, which differs from the secondary structure of the corresponding portion of the native insulin molecule. Tyr16 is required for this adopted structure of the dimerized insulin peptide as well as for the γδ response to it. This observation is consistent with the notion that γδ T cell recognition depends on the secondary structure of the dimerized insulin B:9-23 antigen.

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Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells

Abstract: Monovalent engagement can trigger BCR signal transduction, and fine-tuning of BCR-ligand recognition can lead to B cell nonresponsiveness, activation, or inhibition.

Cited by 58 publications

References 45 publications

Utilization of a photoactivatable antigen system to examine B-cell probing termination and the B-cell receptor sorting mechanisms during B-cell activation

Utilization of a photoactivatable antigen system to examine B-cell probing termination and the B-cell receptor sorting mechanisms during B-cell activation

Molecular Control of B Cell Activation and Immunological Synapse Formation

γδ T cells recognize the insulin B:9–23 peptide antigen when it is dimerized through thiol oxidation

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