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Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis.
Arthritis Rheum. 2007 Mar; 56(3):732-42.AR

Abstract

OBJECTIVE

We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg-mediated suppression.

METHODS

Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25- and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), or IL-7.

RESULTS

Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25- and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg-mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNFalpha, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg-mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression.

CONCLUSION

Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA.

Authors+Show Affiliations

University Medical Center Utrecht, Utrecht, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17328044

Citation

van Amelsfort, Jocea M R., et al. "Proinflammatory Mediator-induced Reversal of CD4+,CD25+ Regulatory T Cell-mediated Suppression in Rheumatoid Arthritis." Arthritis and Rheumatism, vol. 56, no. 3, 2007, pp. 732-42.
van Amelsfort JM, van Roon JA, Noordegraaf M, et al. Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum. 2007;56(3):732-42.
van Amelsfort, J. M., van Roon, J. A., Noordegraaf, M., Jacobs, K. M., Bijlsma, J. W., Lafeber, F. P., & Taams, L. S. (2007). Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis and Rheumatism, 56(3), 732-42.
van Amelsfort JM, et al. Proinflammatory Mediator-induced Reversal of CD4+,CD25+ Regulatory T Cell-mediated Suppression in Rheumatoid Arthritis. Arthritis Rheum. 2007;56(3):732-42. PubMed PMID: 17328044.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. AU - van Amelsfort,Jocea M R, AU - van Roon,Joel A G, AU - Noordegraaf,Madelon, AU - Jacobs,Kim M G, AU - Bijlsma,Johannes W J, AU - Lafeber,Floris P J G, AU - Taams,Leonie S, PY - 2007/3/1/pubmed PY - 2007/4/14/medline PY - 2007/3/1/entrez SP - 732 EP - 42 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 56 IS - 3 N2 - OBJECTIVE: We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg-mediated suppression. METHODS: Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25- and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), or IL-7. RESULTS: Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25- and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg-mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNFalpha, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg-mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression. CONCLUSION: Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/17328044/Proinflammatory_mediator_induced_reversal_of_CD4+CD25+_regulatory_T_cell_mediated_suppression_in_rheumatoid_arthritis_ L2 - https://doi.org/10.1002/art.22414 DB - PRIME DP - Unbound Medicine ER -