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

Nicla Porciello, Paola Grazioli, Antonio F. Campese, Martina Kunkl, Silvana Caristi, Marta Mastrogiovanni, Michela Muscolini, Francesca Spadaro, Cédric Favre, Jacques A. Nunès, Aldo Borroto, Balbino Alarcon, Isabella Screpanti and Loretta Tuosto ()
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Nicla Porciello: Sapienza University
Paola Grazioli: Sapienza University
Antonio F. Campese: Sapienza University
Martina Kunkl: Sapienza University
Silvana Caristi: Sapienza University
Marta Mastrogiovanni: Sapienza University
Michela Muscolini: Istituto Pasteur-Fondazione Cenci Bolognetti
Francesca Spadaro: Istituto Superiore di Sanità
Cédric Favre: Aix-Marseille Université UM 105
Jacques A. Nunès: Aix-Marseille Université UM 105
Aldo Borroto: Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM)
Balbino Alarcon: Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM)
Isabella Screpanti: Sapienza University
Loretta Tuosto: Sapienza University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03385-8

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DOI: 10.1038/s41467-018-03385-8

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