Ellis, SDP;
(2014)
The induction and characterisation of CD8+FOXP3+ regulatory T cells by anti-CD3 mAb in inflammatory arthritis.
Doctoral thesis , UCL (University College London).
Abstract
Limiting the severity of inflammation and promoting its eventual resolution are vital for protecting host tissues both in autoimmunity and inflammation. In this thesis, I describe a potent CD8+FOXP3+ regulatory T cell (Treg) population in patients with rheumatoid and psoriatic arthritis, which can be induced from peripheral blood mononuclear cells after stimulation with different clones of anti-CD3 mAb, including OKT3 and the non Fc-receptor binding antibody otelixizumab. CD8+FOXP3+ Treg inhibited Th17 responses, thereby functioning to limit a wider range of inflammatory pathways compared to CD4+FOXP3+ Treg. They also regulated CD4+ T cell proliferation and Th1 responses. Investigation by microarray into the mechanism of CD8+FOXP3+ Treg mediated suppression revealed several candidate surface markers and cytokines. During investigation into the mechanism of CD8+FOXP3+ Treg induction, I demonstrate a ten-fold induction, not expansion, of these Treg by anti-CD3 monoclonal antibodies. This was supported both by p38 phosphorylation, intrinsic to CD8+ T cells, and by signals provided by monocytes via CD86 and membrane TNF-α. Artificially increasing monocyte membrane TNF-α or inhibiting CD8+ T cell p38 phosphorylation drove FOXP3 expression in a subset of initially unresponsive CD8+ T cells. These data define a previously unknown mechanism of CD8+FOXP3+ Treg induction by anti-CD3 antibodies. Furthermore, anti-CD3 mAb could be combined with a p38 inhibitor to improve the mAb’s therapeutic efficacy and resolve chronic inflammation via the restoration of tolerance. These data also provide a rationale for the repurposing of anti-CD3 mAb as a therapy for inflammatory arthropathies.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The induction and characterisation of CD8+FOXP3+ regulatory T cells by anti-CD3 mAb in inflammatory arthritis |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1432347 |
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