Regulatory T cells in rheumatoid arthritis : contributions from different functional subsets
Author: Herrath, Jessica Alexandra
Date: 2014-09-26
Location: Föreläsningssalen på CMM, L8:00, Karolinska Institutet, Solna
Time: 9:00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
Abstract
Rheumatoid arthritis (RA) is a complex and multifactorial disease characterized by chronic joint inflammation and tissue destruction, which can affect all ethnic groups with a prevalence of 0.5-1%. FOXP3+ regulatory T cells (Treg cells) are crucial for the maintenance of self-tolerance and loss of function or reduced frequencies have been implicated in chronic inflammatory and autoimmune diseases. In patients with inflammatory arthritis including RA, Treg cells are significantly enriched at the site of inflammation compared with levels in the circulation, and are further functional in suppressing autologous effector T cells from both peripheral blood and joint origin. Given the accumulation of functional Treg cells in the rheumatic joint, an unresolved question is why local inflammation processes persist in a chronic way.
In this thesis, we investigated the presence, frequency and functionality of different Treg-cell subsets in patients with inflammatory arthritis, and further studied the impact of commonly used treatment regimes on the suppressive capacity of Treg cells. We could show that synovial FOXP3+ Treg cells were increased in frequency compared with peripheral blood, displayed a high degree of FOXP3 demethylation and a low capacity of secreting pro-inflammatory cytokines upon stimulation. Moreover, the activation status of effector T cells and locally produced pro-inflammatory cytokines reduced regulatory Treg cell function in vitro and presumably in the rheumatic joint.
Furthermore, expression of CD39, an ecto-nucleotidase, which together with CD73 generates anti-inflammatory adenosine, was significantly increased on synovial FOXP3+ Treg cells. Such FOXP3+CD39+ Treg cells did not produce pro-inflammatory cytokines and were good suppressors of several effector T-cell functions including secretion of IFN-γ and TNF, but did not limit IL-17A, a cytokine implicated in RA pathogenesis.
Additional investigations of FOXP3+ Treg cells in the context of Helios, a suggested marker of thymus-derived Treg cells, revealed that synovial Helios+FOXP3+ T cells were abundant in the joint, displayed a more classical Treg-cell phenotype with regard to expression of surface markers and cytokine secretion capacity compared with Helios-FOXP3+ T cells.
Finally, biologicals commonly used for the treatment of RA were shown to have profound effects on Treg-cell function, however by different mechanisms. Blocking of IL-6 and TNF by tocilizumab or adalimumab increased suppressive capacity of synovial Treg cells. Abatacept, in contrast, had no beneficial effect on Treg-cell function, but due to its mutual effect on effector and regulatory T cells, the inflammatory pressure in the joint could still be alleviated.
In summary, our data suggest that joint-derived Treg cells in general are not impaired in their function and rather the inflammatory pressure needs to be reduced to allow for optimal Treg-cell functionality. Further, this work emphasizes the importance of dissecting synovial Treg-cell subsets to gain a better understanding on how Treg cells could be targeted for the treatment of chronic arthritis. ::doi::10.1002/eji.201041004. ::pmid::21607944 ::isi::000293264300019
In this thesis, we investigated the presence, frequency and functionality of different Treg-cell subsets in patients with inflammatory arthritis, and further studied the impact of commonly used treatment regimes on the suppressive capacity of Treg cells. We could show that synovial FOXP3+ Treg cells were increased in frequency compared with peripheral blood, displayed a high degree of FOXP3 demethylation and a low capacity of secreting pro-inflammatory cytokines upon stimulation. Moreover, the activation status of effector T cells and locally produced pro-inflammatory cytokines reduced regulatory Treg cell function in vitro and presumably in the rheumatic joint.
Furthermore, expression of CD39, an ecto-nucleotidase, which together with CD73 generates anti-inflammatory adenosine, was significantly increased on synovial FOXP3+ Treg cells. Such FOXP3+CD39+ Treg cells did not produce pro-inflammatory cytokines and were good suppressors of several effector T-cell functions including secretion of IFN-γ and TNF, but did not limit IL-17A, a cytokine implicated in RA pathogenesis.
Additional investigations of FOXP3+ Treg cells in the context of Helios, a suggested marker of thymus-derived Treg cells, revealed that synovial Helios+FOXP3+ T cells were abundant in the joint, displayed a more classical Treg-cell phenotype with regard to expression of surface markers and cytokine secretion capacity compared with Helios-FOXP3+ T cells.
Finally, biologicals commonly used for the treatment of RA were shown to have profound effects on Treg-cell function, however by different mechanisms. Blocking of IL-6 and TNF by tocilizumab or adalimumab increased suppressive capacity of synovial Treg cells. Abatacept, in contrast, had no beneficial effect on Treg-cell function, but due to its mutual effect on effector and regulatory T cells, the inflammatory pressure in the joint could still be alleviated.
In summary, our data suggest that joint-derived Treg cells in general are not impaired in their function and rather the inflammatory pressure needs to be reduced to allow for optimal Treg-cell functionality. Further, this work emphasizes the importance of dissecting synovial Treg-cell subsets to gain a better understanding on how Treg cells could be targeted for the treatment of chronic arthritis. ::doi::10.1002/eji.201041004. ::pmid::21607944 ::isi::000293264300019
List of papers:
I. The inflammatory milieu in the rheumatic joint reduces regulatory T-cell function Jessica Herrath, Malin Müller, Petra Amoudruz, Peter Janson, Jakob Michaelsson, Per T. Larsson, Christina Trollmo, Sukanya Raghavan and Vivianne Malmström European Journal of Immunology, (2011) vol. 41, pp:2279-2290.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Surface expression of CD39 identifies an enriched Treg-cell subset in the rheumatic joint, which does not suppress IL-17A secretion Jessica Herrath, Karine Chemin, Inka Albrecht, Anca I. Catrina and Vivianne Malmström European Journal of Immunology, (2014).
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Helios+ and Helios-FOXP3+CD4+ T cells in rheumatic joints represent distinct T-cell subsets Malin Müller, Jessica Herrath and Vivianne Malmström. [Manuscript]
IV. CTLA4-Ig (abatacept) therapy modulates T-cell effector functions in autoantibody-positive rheumatoid arthritis patients Jennifer Pieper, Jessica Herrath, Sukanya Raghavan, Khalid Muhammad, Ronald van Vollenhoven and Vivianne Malmström BMC Immunology, 2013, vol. 14:34.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. The inflammatory milieu in the rheumatic joint reduces regulatory T-cell function Jessica Herrath, Malin Müller, Petra Amoudruz, Peter Janson, Jakob Michaelsson, Per T. Larsson, Christina Trollmo, Sukanya Raghavan and Vivianne Malmström European Journal of Immunology, (2011) vol. 41, pp:2279-2290.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Surface expression of CD39 identifies an enriched Treg-cell subset in the rheumatic joint, which does not suppress IL-17A secretion Jessica Herrath, Karine Chemin, Inka Albrecht, Anca I. Catrina and Vivianne Malmström European Journal of Immunology, (2014).
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Helios+ and Helios-FOXP3+CD4+ T cells in rheumatic joints represent distinct T-cell subsets Malin Müller, Jessica Herrath and Vivianne Malmström. [Manuscript]
IV. CTLA4-Ig (abatacept) therapy modulates T-cell effector functions in autoantibody-positive rheumatoid arthritis patients Jennifer Pieper, Jessica Herrath, Sukanya Raghavan, Khalid Muhammad, Ronald van Vollenhoven and Vivianne Malmström BMC Immunology, 2013, vol. 14:34.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Malmström, Vivianne
Issue date: 2014-09-04
Rights:
Publication year: 2014
ISBN: 978-91-7549-545-3
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