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

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

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., ... 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
Clement, Mathew ; Pearson, James A. ; Gras, Stephanie ; Van Den Berg, Hugo A. ; Lissina, Anya ; Llewellyn-Lacey, Sian ; Willis, Mark D ; Docree, 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. / Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies. In: Scientific Reports. 2016 ; Vol. 6.
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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.",
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Clement, M, Pearson, JA, Gras, S, Van Den Berg, HA, Lissina, A, Llewellyn-Lacey, S, Willis, MD, Docree, T, McLaren, JE, Ekeruche-Makinde, J, Gostick, E, Robertson, NP, Rossjohn, J, Burrows, SR, Price, DA, Wong, FS, Peakman, M, Skowera, A & Wooldridge, L 2016, 'Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies', Scientific Reports, vol. 6, 35332. https://doi.org/10.1038/srep35332

Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies. / Clement, Mathew; Pearson, James A.; Gras, Stephanie; Van Den Berg, Hugo A.; Lissina, Anya; Llewellyn-Lacey, Sian; Willis, Mark D; Docree, 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.

In: Scientific Reports, Vol. 6, 35332, 17.10.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies

AU - Clement, Mathew

AU - Pearson, James A.

AU - Gras, Stephanie

AU - Van Den Berg, Hugo A.

AU - Lissina, Anya

AU - Llewellyn-Lacey, Sian

AU - Willis, Mark D

AU - Docree, Tamsin

AU - McLaren, James E

AU - Ekeruche-Makinde, Julia

AU - Gostick, Emma

AU - Robertson, Neil P

AU - Rossjohn, Jamie

AU - Burrows, Scott R

AU - Price, David A

AU - Wong, F Susan

AU - Peakman, Mark

AU - Skowera, Ania

AU - Wooldridge, Linda

PY - 2016/10/17

Y1 - 2016/10/17

N2 - 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.

AB - 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.

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DO - 10.1038/srep35332

M3 - Article

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 35332

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Clement M, Pearson JA, Gras S, Van Den Berg HA, Lissina A, Llewellyn-Lacey S et al. Targeted suppression of autoreactive CD8+ T-cell activation using blocking anti-CD8 antibodies. Scientific Reports. 2016 Oct 17;6. 35332. https://doi.org/10.1038/srep35332