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

Nicla Porciello (1) , Paola Grazioli (2) , Antonio Campese (2, 3) , Martina Kunkl (1) , Silvana Caristi (1) , Marta Mastrogiovanni (1) , Michela Muscolini (4) , Francesca Spadaro (5) , Cédric Favre (6, 7) , Jacques Nunes (6) , Aldo Borroto (8) , Balbino Alarcon (8) , Isabella Screpanti (3) , Loretta Tuosto (1)

1 Department of Biology and Biotechnology "Charles Darwin"
2 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
3 Department of Molecular Medicine
4 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti
5 ISS - Istituto Superiore di Sanità = National Institute of Health
6 CRCM - Centre de Recherche en Cancérologie de Marseille
7 Immunotech-Beckman Coulter
8 CBMSO - Centro de Biología Molecular Severo Ochoa [Madrid]

CD28 superagonistic antibodies (CD28SAb) can preferentially activate and expand immu-nosuppressive 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 (P 212 in human vs. A 210 in mouse) regulates CD28-induced NF-κB activation and pro-inflammatory cytokine gene expression. Moreover, this Y 209 APP 212 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.

Mots clés: CD4-positive T cells; Autoimmune diseases; Signal transduction; NF-kappaB

Domaines: Immunologie

Nicla Porciello, Paola Grazioli, Antonio Campese, Martina Kunkl, Silvana Caristi, et al.. A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nature Communications, 2018, 9 (1), pp.1080. ⟨10.1038/s41467-018-03385-8⟩. ⟨hal-01772994⟩