CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immunosuppressive regulatory T cells (Treg) in mice. However, pre-clinical trials assessing CD28SAbs for the therapy of autoimmune diseases reveal severe systemic inflammatory response syndrome in humans, thereby implying the existence of distinct signalling abilities between human and mouse CD28. Here, we show that a single amino acid variant within the C-terminal proline-rich motif of human and mouse CD28 (P212 in human vs. A210 in mouse) regulates CD28-induced NF-κB activation and pro-inflammatory cytokine gene expression. Moreover, this Y209APP212 sequence in humans is crucial for the association of CD28 with the Nck adaptor protein for actin cytoskeleton reorganisation events necessary for CD28 autonomous signalling. This study thus unveils different outcomes between human and mouse CD28 signalling to underscore the importance of species difference when transferring results from preclinical models to the bedside.

A non-conserved amino acid variant regulates differential signalling between human and mouse CD28 / Porciello, Nicla; Grazioli, Paola; Campese, Antonio F.; Kunkl, Martina; Caristi, Silvana; Mastrogiovanni, Marta; Muscolini, Michela; Spadaro, Francesca; Favre, Cédric; Nunès, Jacques A.; Borroto, Aldo; Alarcon, Balbino; Screpanti, Isabella; Tuosto, Loretta. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - ELETTRONICO. - 9:1(2018), pp. 1-16. [10.1038/s41467-018-03385-8]

A non-conserved amino acid variant regulates differential signalling between human and mouse CD28

Porciello, Nicla
Primo
Investigation
;
Grazioli, Paola
Secondo
Investigation
;
Campese, Antonio F.
Investigation
;
Kunkl, Martina
Investigation
;
Caristi, Silvana
Investigation
;
Mastrogiovanni, Marta
Investigation
;
Muscolini, Michela
Investigation
;
Screpanti, Isabella
Penultimo
Writing – Review & Editing
;
Tuosto, Loretta
Ultimo
Writing – Original Draft Preparation
2018

Abstract

CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immunosuppressive regulatory T cells (Treg) in mice. However, pre-clinical trials assessing CD28SAbs for the therapy of autoimmune diseases reveal severe systemic inflammatory response syndrome in humans, thereby implying the existence of distinct signalling abilities between human and mouse CD28. Here, we show that a single amino acid variant within the C-terminal proline-rich motif of human and mouse CD28 (P212 in human vs. A210 in mouse) regulates CD28-induced NF-κB activation and pro-inflammatory cytokine gene expression. Moreover, this Y209APP212 sequence in humans is crucial for the association of CD28 with the Nck adaptor protein for actin cytoskeleton reorganisation events necessary for CD28 autonomous signalling. This study thus unveils different outcomes between human and mouse CD28 signalling to underscore the importance of species difference when transferring results from preclinical models to the bedside.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/1086397
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