Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies

CD8+ T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8+ T-cell population are not desirable because these cells protect against invading pathogens. Accordingly, there is a need to develop novel therapeutics that exclusively target autoreactive CD8+ T-cells. Here, we show that autoreactive CD8+ T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8+ T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, “blocking” anti-CD8 antibodies may have the potential to halt autoreactive CD8+ T-cell activation in a selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that specifically target disease-relevant autoimmune responses within the CD8+ T-cell compartment