TY - JOUR
T1 - A non-conserved amino acid variant regulates differential signalling between human and mouse CD28
AU - Porciello, Nicla
AU - Grazioli, Paola
AU - Campese, Antonio F.
AU - Kunkl, Martina
AU - Caristi, Silvana
AU - Mastrogiovanni, Marta
AU - Muscolini, Michela
AU - Spadaro, Francesca
AU - Favre, Cédric
AU - Nunès, Jacques A.
AU - Borroto, Aldo
AU - Alarcon, Balbino
AU - Screpanti, Isabella
AU - Tuosto, Loretta
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-018-03385-8
DO - 10.1038/s41467-018-03385-8
M3 - Article
C2 - 29540686
AN - SCOPUS:85044238727
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1080
ER -