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