Autoreactive CD4+ and CD8+ T cells play a critical role in the pathophysiology of autoimmune diseases such as Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) by sustaining a chronic inflammatory process that takes place in the central nervous system and in the joints, respectively.
Bacterial infections provoked by Staphylococcus aureus have been brought up as critical environmental factors that may trigger and/or exacerbate MS and RA. Interestingly, this pathogen shares the ability to produce or induce the production of toxin superantigens (SAgs), which can trigger an inflammatory cytokine storm thanks to their unique ability to bind MHC class II molecules on antigen presenting cells and specific elements within the variable domain of the T-cell receptor (TCR) ß-chain (Vß) on T cells, thus inducing the polyclonal activation of T cells. Therefore, S. aureus SAgs can play a dual role in the pathogenesis of autoimmune diseases either by initiating the autoimmune process or by inducing a relapse in patients in clinical remission phases.
CD28 is a critical costimulatory receptor that ensures a full T cell activation and an optimal response to microbes. Recent studies, have identified CD28 as an additional SAg ligand able to elicit an inflammatory cytokine storm. Importantly, short mimetic peptides targeting the CD28 homodimer interface and inhibiting the CD28/B7 interaction, were effective in dampening inflammatory cytokine production induced by S aureus SAgs without affecting the immune response to pathogens. Therefore, selective targeting of the CD28/B7 costimulatory axis through mimetic peptides may provide a novel strategy for preventing the activation of inflammatory T cells mediated by SAg in MS and RA.
The aim of this project will be to analyse the contribution of CD28 and SAgs in regulating the expansion of specific T cells in MS and RA patients and to assess the inhibitory effects of CD28 homodimer interface mimetic peptides.