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B cell receptor ligation induces display of V-region peptides on MHC class II molecules to T cells.

ABSTRACT: The B cell receptors (BCRs) for antigen express variable (V) regions that are enormously diverse, thus serving as markers on individual B cells. V region-derived idiotypic (Id) peptides can be displayed as pId:MHCII complexes on B cells for recognition by CD4+ T cells. It is not known if naive B cells spontaneously display pId:MHCII in vivo or if BCR ligation is required for expression, thereby enabling collaboration between Id+ B cells and Id-specific T cells. Here, using a mouse model, we show that naive B cells do not express readily detectable levels of pId:MHCII. However, BCR ligation by Ag dramatically increases physical display of pId:MHCII, leading to activation of Id-specific CD4+ T cells, extrafollicular T-B cell collaboration and some germinal center formation, and production of Id+ IgG. Besides having implications for immune regulation, the results may explain how persistent activation of self-reactive B cells induces the development of autoimmune diseases and B cell lymphomas.

SUBMITTER: Huszthy PC

PROVIDER: S-EPMC6926052 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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B cell receptor ligation induces display of V-region peptides on MHC class II molecules to T cells.

Huszthy Peter Csaba PC Gopalakrishnan Ramakrishna Prabhu RP Jacobsen Johanne Tracey JT Haabeth Ole Audun Werner OAW Løset Geir Åge GÅ Braathen Ranveig R Schenck Karl K Tveita Anders Aune AA Munthe Ludvig Andre LA Bogen Bjarne B

Proceedings of the National Academy of Sciences of the United States of America 20191203 51

The B cell receptors (BCRs) for antigen express variable (V) regions that are enormously diverse, thus serving as markers on individual B cells. V region-derived idiotypic (Id) peptides can be displayed as pId:MHCII complexes on B cells for recognition by CD4<sup>+</sup> T cells. It is not known if naive B cells spontaneously display pId:MHCII in vivo or if BCR ligation is required for expression, thereby enabling collaboration between Id<sup>+</sup> B cells and Id-specific T cells. Here, using ...[more]

PMID: 31796587

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Project description:BackgroundPeptides binding to Major Histocompatibility Complex (MHC) class II molecules are crucial for initiation and regulation of immune responses. Predicting peptides that bind to a specific MHC molecule plays an important role in determining potential candidates for vaccines. The binding groove in class II MHC is open at both ends, allowing peptides longer than 9-mer to bind. Finding the consensus motif facilitating the binding of peptides to a MHC class II molecule is difficult because of different lengths of binding peptides and varying location of 9-mer binding core. The level of difficulty increases when the molecule is promiscuous and binds to a large number of low affinity peptides. In this paper, we propose two approaches using multi-objective evolutionary algorithms (MOEA) for predicting peptides binding to MHC class II molecules. One uses the information from both binders and non-binders for self-discovery of motifs. The other, in addition, uses information from experimentally determined motifs for guided-discovery of motifs.ResultsThe proposed methods are intended for finding peptides binding to MHC class II I-Ag7 molecule - a promiscuous binder to a large number of low affinity peptides. Cross-validation results across experiments on two motifs derived for I-Ag7 datasets demonstrate better generalization abilities and accuracies of the present method over earlier approaches. Further, the proposed method was validated and compared on two publicly available benchmark datasets: (1) an ensemble of qualitative HLA-DRB1*0401 peptide data obtained from five different sources, and (2) quantitative peptide data obtained for sixteen different alleles comprising of three mouse alleles and thirteen HLA alleles. The proposed method outperformed earlier methods on most datasets, indicating that it is well suited for finding peptides binding to MHC class II molecules.ConclusionWe present two MOEA-based algorithms for finding motifs, one for self-discovery and the other for guided-discovery by experimentally determined motifs, and thereby predicting binding peptides to I-Ag7 molecule. Our experiments show that the proposed MOEA-based algorithms are better than earlier methods in predicting binding sites not only on I-Ag7 but also on most alleles of class II MHC benchmark datasets. This shows that our methods could be applicable to find binding motifs in a wide range of alleles.

Dataset Information

B cell receptor ligation induces display of V-region peptides on MHC class II molecules to T cells.

Publications

B cell receptor ligation induces display of V-region peptides on MHC class II molecules to T cells.

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