Understanding Early Events of B Cell Antigen Receptor Activation: Effects of Antigen and Receptor Valency

by Erdem Yilmaz
Doctoral thesis
Date of Examination:2024-12-16
Date of issue:2025-03-07
Advisor:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Jürgen Wienands
Referee:Prof. Dr. Ivan Bogeski
Referee:Prof. Dr. Nils Brose
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Ralf Dressel
Referee:Prof. Dr. Heidi Hahn
Persistent Address: http://dx.doi.org/10.53846/goediss-11128

 

 

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Abstract

English

Abstract Each B cell is equipped with B cell antigen receptors (BCRs) of a unique specificity. These BCRs are crucial in many events including B cell development, activation and differentiation. There is still an ongoing debate on how BCRs are distributed on cell surfaces of B cells in resting and stimulated conditions and how this distribution is affected by antigens of different valencies. In this study, I demonstrated that both antigen valency and BCR valency are important in BCR clustering and subsequent BCR activation. Quantitative stimulated emission depletion (STED) imaging analysis showed that upon stimulation, BCRs form clusters in the plasma membrane and the size of clusters (i.e. the number of BCRs in the clusters) dictates the level of intracellular signaling and BCR endocytosis. These data also suggest that BCR divalency is crucial in response to low valency antigens, thus providing an explanation why evolution maintained the BCR bivalency with two antigen binding sites. BCRs harboring additional ITAMs in their heavy chains (HCs) are chronically active, leading to constitutive phosphorylation of spleen tyrosine kinase (Syk), one of the master kinases in BCR signaling. Hence, these chronically active BCRs become partially desensitized and cannot initiate signaling upon antigen binding, indicating BCR pre-clustering has a negative effect on BCR activation. This study revealed that BCR activation mechanisms may vary depending on also the BCR isotype; mIgG-BCRs require a crosslinking ligand for activation, whereas mIgM- BCRs can be activated by both crosslinking ligands and monovalent ligands.
Keywords: B cell antigen receptor; Activation of B cell antigen receptor; Valency of antigens; Valency of B cell antigen receptors
Schlagwörter: English
 
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