Rheumatoid arthritis (RA) is a chronic inflammatory immune disease affecting the joints. CD4+CD25+ regulatory T cells (Tregs) are abundantly present in the inflamed joints of patients with RA, but inflammation still persists. The notion that Tregs are terminally differentiated suppressor cells has recently been disputed by studies showing that Tregs can display a significant degree of plasticity and even convert into IL-17-producing cells under inflammatory conditions. Therefore, the overall hypothesis of this thesis was that the pro-inflammatory environment impairs Treg function in RA by converting them into IL-17-producing cells. We show in this thesis that frequencies of CD25+CD127low Tregs with a CD45RO+ memory phenotype were increased at the site of inflammation in RA. These Tregs displayed a regulatory phenotype, with increased expression of the Th17 marker CD161. Furthermore, CD14+ monocytes with an activated phenotype were found in high numbers in the RA joint. Monocytes and Tregs could be found in close proximity in human tissue suggesting that they interact in vivo. We next studied the effects of in vitro-activated monocytes on Treg phenotype and function. Activated monocytes increased the percentages of IL-17+, IFNγ+, TNF-α+, and IL-10+ memory (CD45RA-) Tregs. Tregs from these co-cultures showed no loss in Treg markers or suppressive capacity, and were rather enhanced in their suppressor functions. Finally, Tregs from the peripheral blood of patients with RA showed a similar phenotype and cytokine expression profile compared to Tregs from healthy controls. RA Tregs were capable of suppressing autologous effector T cell proliferation and cytokine secretion. However, Tregs from some patients showed a hampered ability to suppress monocyte-derived chemokines and cytokines. Together, these data suggest that Treg function is not globally impaired in patients with RA and that Tregs exposed to a pro-inflammatory environment, such as occurs in the inflamed rheumatic joint, do not lose their regulatory function.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634163 |
| Date | January 2013 |
| Creators | Walter, Gina |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/do-activated-monocytes-impair-regulatory-t-cell-function-in-rheumatoid-arthritis(bec96e89-858a-42a3-87cf-6167ee9d633e).html |
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