A non-conserved amino acid variant regulates differential signalling between human and mouse CD28.
Nicla PorcielloPaola GrazioliAntonio F CampeseMartina KunklSilvana CaristiMarta MastrogiovanniMichela MuscoliniFrancesca SpadaroCédric FavreJacques A NunèsAldo BorrotoBalbino AlarconIsabella ScrepantiLoretta TuostoPublished in: Nature communications (2018)
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.
Keyphrases
- endothelial cells
- gene expression
- amino acid
- inflammatory response
- regulatory t cells
- clinical trial
- induced pluripotent stem cells
- pluripotent stem cells
- dna methylation
- signaling pathway
- transcription factor
- small molecule
- immune response
- metabolic syndrome
- lps induced
- early onset
- mesenchymal stem cells
- toll like receptor
- adipose tissue
- cell therapy
- binding protein
- skeletal muscle
- phase iii
- double blind
- placebo controlled