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

Mathew Clement, James A Pearson, Stephanie Gras, Hugo A van den Berg, Anya Lissina, Sian Llewellyn-Lacey, Mark D Willis, Tamsin Dockree, James E McLaren, Julia Ekeruche-Makinde, Emma Gostick, Neil P Robertson, Jamie Rossjohn, Scott R Burrows, David A Price, F Susan Wong, Mark Peakman, Ania Skowera, Linda Wooldridge

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22 Citations (Scopus)
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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.

Original languageEnglish
Article number35332
JournalScientific Reports
Volume6
Early online date17 Oct 2016
DOIs
Publication statusE-pub ahead of print - 17 Oct 2016

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