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

Citations Over TimeTop 21% of 2016 papers

Abstract

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 the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. 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 can suppress autoreactive CD8+ T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8+ T-cell compartment.

Related Papers

• → T Cell Receptor Signaling Is Limited by Docking Geometry to Peptide-Major Histocompatibility Complex(2011)261 cited
• → Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability(2010)114 cited
• → Current status and future challenges in T-cell receptor/peptide/MHC molecular dynamics simulations(2015)56 cited
• → Molecular modeling of a T-cell receptor bound to a major histocompatibility complex molecule: Implications for T-cell recognition(1995)12 cited
• → Engagement of a T cell receptor by major histocompatibility complex irrespective of peptide(1997)7 cited