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 Docree, 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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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
Number of pages14
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 17 Oct 2016

Cite this

Clement, M., Pearson, J. A., Gras, S., Van Den Berg, H. A., Lissina, A., Llewellyn-Lacey, S., Willis, M. D., Docree, T., McLaren, J. E., Ekeruche-Makinde, J., Gostick, E., Robertson, N. P., Rossjohn, J., Burrows, S. R., Price, D. A., Wong, F. S., Peakman, M., Skowera, A., & Wooldridge, L. (2016). Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies. Scientific Reports, 6, [35332]. https://doi.org/10.1038/srep35332