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dc.contributor.authorWallberg, Majaen
dc.contributor.authorRecino, Aen
dc.contributor.authorPhillips, Jen
dc.contributor.authorHowie, Den
dc.contributor.authorVienne, Men
dc.contributor.authorPaluch, Cen
dc.contributor.authorAzuma, Men
dc.contributor.authorWong, FSen
dc.contributor.authorWaldmann, Hen
dc.contributor.authorCooke, Anneen
dc.date.accessioned2017-05-02T16:50:15Z
dc.date.available2017-05-02T16:50:15Z
dc.date.issued2017-03-16en
dc.identifier.issn0019-2805
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/263966
dc.description.abstractT cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)+ islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time-points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti-CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon-γ. Programmed cell death protein 1 (PD-1) expression was up-regulated on the effector cells from anti-CD3-treated mice, and diabetes induced through anti-PD-L1 antibody could only be reversed with anti-CD3 antibody if the anti-CD3 treatment lasted beyond the point when the anti-PD-L1 antibody was washed out of the system. This suggests that PD-1/PD-L1 interaction plays an important role in the anti-CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti-CD3 therapy can reverse diabetogenesis.
dc.description.sponsorshipThis work was funded by grants from the National Centre for the Replacement, Refinement and Reduction of Animals in research (NC3Rs) (NC/M001083/1) (MW), Diabetes UK (BDA 13/0004785) (AC), Diabetes Research and Wellness (SCA/OF/12/13) (AC), European Research Council 7th Frame Programme (health-f5-2009-241883) (AC and HW), Britain Israel Research and Academic Exchange Partnership (BIRAX) (02BX12ACYD) (AC), and ERC advanced investigator grant 339402 (HW) and pump priming funding from the Cambridge University Isaac Newton trust.
dc.languageengen
dc.language.isoenen
dc.publisherWiley
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectdiabetesen
dc.subjecttransgenic/knockout mouseen
dc.subjecttolerance/suppression/anergyen
dc.subjectantibodiesen
dc.titleAnti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacityen
dc.typeArticle
prism.publicationDate2017en
prism.publicationNameImmunologyen
dc.identifier.doi10.17863/CAM.9341
dcterms.dateAccepted2017-02-13en
rioxxterms.versionofrecord10.1111/imm.12729en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc/4.0/en
rioxxterms.licenseref.startdate2017-03-16en
dc.contributor.orcidCooke, Anne [0000-0003-3327-6081]
dc.identifier.eissn1365-2567
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idNC3Rs (NC/M001083/1)
pubs.funder-project-idDiabetes UK (DUK-13/0004785)
cam.issuedOnline2017-02-17en


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Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial 4.0 International