CD40 blockade hampers IgG class-switch while enhancing Granzyme B production by transitional B cells

Werner F, Wittner J, Lehmann C, Wahlbuhl-Becker M, Allabauer I, Hoffmann A, Schnell A, Krickau T, Hackstein H, Dietel-Schor B, Rush JS, Regnier CH, Jäck HM, Wölfle J, Schuh W, Hörning A (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Clinical and Experimental Immunology Wiley-Blackwell

Article Number: uxaf044

DOI: 10.1093/cei/uxaf044

Abstract

CD40-CD40L interaction is crucial for the interplay between B and T cells and determines B cell fate. Here, we investigated the effects of CD40-CD40L inhibition on B cell subsets and cytokine production using the non-depleting monoclonal anti-CD40 antibody CFZ534. CFZ534 had no impact on B cell viability but inhibited TLR9-agonistic (CpG-ODN) CD40L- as well as CD40L-mediated proliferation. The plasmablast subset was reduced after stimulation with CpG-ODN+CD40L but this effect was completely restored by CFZ534-mediated CD40 blockade. IgG as well as IgM-secreting cells were significantly reduced in the presence of CFZ534 upon CD40L stimulation. CpG-ODN, but not CD40L, induced Granzyme B production in B cells after CD40-blockade and CpG-ODN/CD40L stimulation. Moreover, we found that IL-10 and Granzyme B were produced by separate B cell subsets. Hence, CD40-blockade mediated by CFZ534 increased Granzyme B production and decreased IL-10 production in CD24hiCD38hi B cells with a transitional phenotype and led to a significant decrease in the expression of the pro-inflammatory cytokines IL-6, IL-12p35 and IL-23p19 and TNFα in a B and CD4+ TH-cell co-culture system. Based on these pre-clinical results CD40 blockade by the Fc-silent, non-depleting monoclonal antibody CFZ534 exerts an anti-inflammatory effect on B cells including hampering the IgG class switch without affecting their viability.

Authors with CRIS profile

Felix Werner Institute of General Practice Jens Wittner Department of Molecular Immunology Christian Lehmann Department of Paediatrics and Adolescent Medicine Mandy Wahlbuhl-Becker Department of Paediatrics and Adolescent Medicine Alexander Schnell Department of Paediatrics and Adolescent Medicine Tobias Krickau Department of Paediatrics and Adolescent Medicine Holger Hackstein Professur für Transfusionsmedizin und Cell-Engineering Hans-Martin Jäck Professur für Immunologie Joachim Wölfle Lehrstuhl für Kinder- und Jugendmedizin Wolfgang Schuh Department of Molecular Immunology André Hörning Department of Paediatrics and Adolescent Medicine

Involved external institutions

Novartis AG CH Switzerland (CH)

How to cite

APA:

Werner, F., Wittner, J., Lehmann, C., Wahlbuhl-Becker, M., Allabauer, I., Hoffmann, A.,... Hörning, A. (2025). CD40 blockade hampers IgG class-switch while enhancing Granzyme B production by transitional B cells. Clinical and Experimental Immunology. https://doi.org/10.1093/cei/uxaf044

MLA:

Werner, Felix, et al. "CD40 blockade hampers IgG class-switch while enhancing Granzyme B production by transitional B cells." Clinical and Experimental Immunology (2025).

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