CD40-targeted peptide proposed for type 1 diabetes therapy lacks relevant binding affinity to its cognate receptor. Reply to Pagni PP, Wolf A, Lo Conte M et al [letter]

Vaitaitis, Gisela M.; Olmstead, Michael H.; Waid, Dan; Carter, Jessica R.; Wagner, David H.

doi:10.1007/s00125-019-4945-7

Cited by 3 publications

(2 citation statements)

References 8 publications

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“…Recently, Coppieters and co-workers raised doubts regarding these claims in a letter [3]. Wagner and colleagues countered this in a response highlighting the complex nature of this interaction and the lack of in cellulo data [4].…”

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confidence: 99%

“…Finally, we also performed an activity test using an in vitro cell assay, which was not performed by Coppieters and colleagues [3], and is important since the CD40-CD40L interaction is indeed complex, as argued by Wagner and co-workers [4], and simple interaction-blocking assays may not yield relevant characterisation. Using the same (human) HEK Blue CD40L sensor cells that quantify NF-κB activation following CD40 stimulation (InvivoGen, San Diego, CA, USA, cat.…”

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confidence: 99%

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CD40-targeting KGYY15 peptides do not efficiently block the CD40–CD40L interaction

Bojadzic

Buchwald

2019

Diabetologia

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confidence: 99%

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confidence: 99%

CD40-targeting KGYY15 peptides do not efficiently block the CD40–CD40L interaction

Bojadzic

Buchwald

2019

Diabetologia

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Modulating CD40 and integrin signaling in the proinflammatory nexus using a 15-amino-acid peptide, KGYY15

Vaitaitis¹,

Wagner²

2023

Journal of Biological Chemistry

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Mechanotransduction governs CD40 function and underlies X-linked Hyper IgM syndrome

Choi,

Travaglino,

Münchhalfen

et al. 2023

Preprint

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B cell maturation in germinal centers (GCs) depends on cognate interactions between the T and B cells. Upon interaction with CD40 ligand (CD40L) on T cells, CD40 delivers co-stimulatory signals alongside B cell antigen receptor (BCR) signaling to regulate affinity maturation and antibody class-switch during GC reaction. Mutations in CD40L disrupt interactions with CD40, which lead to abnormal antibody responses in immune deficiencies known as X-linked Hyper IgM syndrome (X-HIgM). Assuming that physical interactions between highly mobile T and B cells generate mechanical forces on CD40–CD40L bonds, we set out to study the B cell mechanobiology mediated by CD40–CD40L interaction. Using a suite of biophysical assays we find that CD40 forms catch bond with CD40L where the bond lasts longer at larger forces, B cells exert tension on CD40–CD40L bonds, and force enhances CD40 signaling and antibody class-switch. Significantly, X-HIgM CD40L mutations impair catch bond formation, suppress endogenous tension, and reduce force-enhanced CD40 signaling, leading to deficiencies in antibody class switch. Our findings highlight the critical role of mechanotransduction in CD40 function and provide insights into the molecular mechanisms underlying X-HIgM syndrome.

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CD40-targeted peptide proposed for type 1 diabetes therapy lacks relevant binding affinity to its cognate receptor. Reply to Pagni PP, Wolf A, Lo Conte M et al [letter]

Cited by 3 publications

References 8 publications

CD40-targeting KGYY15 peptides do not efficiently block the CD40–CD40L interaction

CD40-targeting KGYY15 peptides do not efficiently block the CD40–CD40L interaction

Modulating CD40 and integrin signaling in the proinflammatory nexus using a 15-amino-acid peptide, KGYY15

Mechanotransduction governs CD40 function and underlies X-linked Hyper IgM syndrome

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