Nadkarni, SA; (2008) Regulatory T cells in rheumatoid arthritis: Clinical relevance and mechanisms in disease. Doctoral thesis , UCL (University College London).

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Abstract

The current work aimed to look at both phenotypic and functional differences in regulatory T cells (Tregs) from active rheumatoid arthritis (RA) patients compared to healthy controls and RA patients receiving infliximab therapy. There was an increase in the number Foxp3+ Tregs in infliximab patients compared to healthy controls or active RA patients. Etanercept patients had similar Foxp3 levels to healthy controls. Active RA Tregs expressed significantly lower levels of CCR5, whilst CD40L was significantly up regulated. Analysis of CTLA-4 in active RA Tregs revealed differential results: CTLA-4 was up regulated on CD4+CD25hl cells, but significantly down regulated on CD4+Foxp3+ Tregs. Furthermore, CTLA-4 remained low in infliximab-treated RA patients. Addition of recombinant TNF-a led to healthy Tregs phenotypically resembling active RA Tregs with respect to the markers described above. Interestingly, Tregs from intliximab-treated patients were predominantly CD62L, in contrast to Tregs from active RA patients and healthy controls. CD62L" Tregs from infliximab patients were found to be more potent suppressors of T effector proliferation and cytokine production, than their CD62L+ counterparts. Additionally, blockade of TGF-P and IL-10 abrogated their suppressive capacity, whereas healthy Tregs suppressed independently of these cytokines. Active RA Tregs and CD62L+, but not CD62L" Tregs from infliximab patients produced comparable levels of IL-17. In vitro addition of infliximab to RA T effectors induced functionally suppressive Foxp3+ T cells, an effect not observed in healthy T effectors. Moreover, blockade of TGF-P in these // vitro cultures inhibited infliximab-induced Foxp3+. Finally, analysis of the TGF-P signalling pathway in RA T effectors demonstrated that these cells expressed significantly lower levels of TGF-p receptor II, and decreased Smad2 phosphorylation, but not total protein. Taken together, the current work demonstrates that active RA Tregs are phenotypically abnormal, which may partly explain their defective function. Moreover, infliximab therapy does not appear to simply restore the defect in the existing conventional Treg (CD62L+) population, but rather induces a distinct population, which differs both phenotypically and functionally, suggesting that altering the pro-inflammatory environment is an important mechanism to restore tolerance.

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