An Ia-restricted epitope-specific circuit regulating T cell-B cell interaction and antibody specificity

Berzofsky, Jay A.

doi:10.1007/bf02918417

Cited by 77 publications

(4 citation statements)

References 23 publications

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“…1h). In the lymph node, T h cells aid the maturation of B cells through a direct-contact process called T-B reciprocity (18)(19)(20). Therefore, for each B cell, we counted the number of T h cells that are in the B cell's vicinity vs T h cells that are not (adjacency distance cutoff = 100µm).…”

Section: Srts Reveal Cccs In the Tissue Microenvironmentmentioning

confidence: 99%

Mapping Cellular Interactions from Spatially Resolved Transcriptomics Data

Zhu,

Wang,

Chang

et al. 2023

Preprint

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An accurate characterization of cell-cell communication (CCC) in the local tissue microenvironment is critical for elucidating the diverse biological processes that coordinate normal physiological development and disease progression. Emerging spatially resolved transcriptomics (SRT) techniques provide rich information on gene expression and cell locations that enable detection of CCC in their spatial context at unprecedented resolution. Here, we introduce a Bayesian framework, spacia, to detect CCC from SRT data, by fully exploiting their unique spatial modality, which dramatically increased the accuracy of the detection of CCC. We highlight spacia's power to overcome fundamental limitations of popular single-cell RNA sequencing-based tools for inference of CCC, which lose single-cell resolution of CCCs and suffer from high false positive rates. Spacia unveiled how various types of cells in the tumor microenvironment differentially contribute to Epithelial-Mesenchymal Transition and lineage plasticity in tumor cells in a prostate cancer MERSCOPE dataset. We deployed spacia in a set of pan-cancer MERSCOPE datasets and derived a signature for measuring the impact of PDL1 on receiving cells from PDL1-positive sending cells. We showed that this signature is associated with patient survival and response to immune checkpoint inhibitor treatments in 3,354 patients. Overall, spacia represents a notable step in advancing quantitative theories of cellular communications.

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Section: Srts Reveal Cccs In the Tissue Microenvironmentmentioning

confidence: 99%

Mapping Cellular Interactions from Spatially Resolved Transcriptomics Data

Zhu,

Wang,

Chang

et al. 2023

Preprint

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“…Pioneer work by Berzofsky and Celada indicated that antibody binding could differentially boost antigen presentation to some T cell clones, either through modulation of antigen uptake or proteolytic processing [51][52][53][54] . Accordingly, it was hypothesized that the antibody specificity shapes the initial pattern of antigen fragmentation, supporting the existence of T and B cell preferential pairing 51,55 and reciprocity circuits 51 . Few years later, elegant work from P.D.…”

Section: Bcr and Antibody Modulation Of Antigen Presentationmentioning

confidence: 99%

“…In particular, antibody-antigen complexes can resist the lysosomal acidic pH 22 , therefore influencing the antigen fragmentation by proteases, which can initiate while the antigen is still bound by antibodies 50 . Pioneer work by Berzofsky and Celada indicated that antibody binding could differentially boost antigen presentation to some T cell clones, either through modulation of antigen uptake or proteolytic processing [51][52][53][54] . Accordingly, it was hypothesized that the antibody specificity shapes the initial pattern of antigen fragmentation, supporting the existence of T and B cell preferential pairing 51,55 and reciprocity circuits 51 .…”

Section: Bcr and Antibody Modulation Of Antigen Presentationmentioning

confidence: 99%

Relative positioning of B and T cell epitopes drives immunodominance

Biavasco

Giovanni

2022

Preprint

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Humoral immunity is crucial for protection against invading pathogens. Broadly neutralizing antibodies (bnAbs) provide sterilizing immunity by targeting conserved regions of viral variants and represent the goal of most vaccination approaches. While antibodies can be selected to bind virtually any region of a given antigen, consistent induction of bnAbs in the context of influenza and HIV has been representing a major roadblock. Many possible explanations have been considered, however, none of the arguments proposed so far seems to fully recapitulate the observed counter-selection for broadly protective antibodies. Antibodies can influence antigen presentation by enhancing the processing of CD4 epitopes adjacent to the binding region while suppressing the overlapping ones. We analyzed the relative positioning of dominant B and T cell epitopes in published antigens that elicit strong and poor humoral responses. In strong immunogenic antigens, regions bound by immunodominant antibodies are frequently adjacent to CD4 epitopes, potentially boosting their presentation. Conversely, poorly immunogenic regions targeted by bnAbs in HIV and influenza overlap with clusters of dominant CD4 epitopes, potentially conferring an intrinsic disadvantage for bnAb-bearing B cells in germinal centers. Here we propose the theory of immunodominance relativity, according to which relative positioning of immunodominant B and CD4 epitopes within a given antigen drives immunodominance. Thus, we suggest that relative positioning of B-T epitopes may be one additional mechanism that cooperates with other previously described processes to influence immunodominance. If demonstrated, this theory can improve the current understanding of immunodominance, provide a novel explanation on HIV and influenza escape from humoral responses, and pave the way for new rational design of universal vaccines.

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“…B-cell receptors (BCRs) recognize diverse epitopes on antigen proteins and control the activation and maturation of B cells [1][2][3][4] . B cells with mature BCRs differentiate into plasma cells that secrete antibodies, which are the secreted forms of BCRs and carry out a variety of functions, such as neutralization of invading pathogens 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data

Song,

Wang,

et al. 2024

Preprint

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The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

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An Ia-restricted epitope-specific circuit regulating T cell-B cell interaction and antibody specificity

Cited by 77 publications

References 23 publications

Mapping Cellular Interactions from Spatially Resolved Transcriptomics Data

Mapping Cellular Interactions from Spatially Resolved Transcriptomics Data

Relative positioning of B and T cell epitopes drives immunodominance

Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data

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