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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 the associated lack of specificity can lead to unwanted consequences, most notably an enhance...

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Detalles Bibliográficos
Autores principales: Clement, Mathew, Pearson, James A., Gras, Stephanie, van den Berg, Hugo A., Lissina, Anya, Llewellyn-Lacey, Sian, Willis, Mark D., Dockree, Tamsin, McLaren, James E., Ekeruche-Makinde, Julia, Gostick, Emma, Robertson, Neil P., Rossjohn, Jamie, Burrows, Scott R., Price, David A., Wong, F. Susan, Peakman, Mark, Skowera, Ania, Wooldridge, Linda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066216/
https://www.ncbi.nlm.nih.gov/pubmed/27748447
http://dx.doi.org/10.1038/srep35332
Descripción
Sumario: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.