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; Loretta Tuosto

doi:10.1038/s41467-018-03385-8

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, Loretta Tuosto

Istituto Superiore di Sanita'

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	1080
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03385-8
Publication status	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Porciello, N., Grazioli, P., Campese, A. F., Kunkl, M., Caristi, S., Mastrogiovanni, M., Muscolini, M., Spadaro, F., Favre, C., Nunès, J. A., Borroto, A., Alarcon, B., Screpanti, I., & Tuosto, L. (2018). A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nature Communications, 9(1), [1080]. https://doi.org/10.1038/s41467-018-03385-8

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, Vol. 9, No. 1, 1080, 01.12.2018.

Research output: Contribution to journal › Article › peer-review

Porciello, N, Grazioli, P, Campese, AF, Kunkl, M, Caristi, S, Mastrogiovanni, M, Muscolini, M, Spadaro, F, Favre, C, Nunès, JA, Borroto, A, Alarcon, B, Screpanti, I & Tuosto, L 2018, 'A non-conserved amino acid variant regulates differential signalling between human and mouse CD28', Nature Communications, vol. 9, no. 1, 1080. https://doi.org/10.1038/s41467-018-03385-8

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. / A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. In: Nature Communications. 2018 ; Vol. 9, No. 1.

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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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