促炎介质诱导类风湿关节炎中CD4 +、CD25 +调节性T细胞介导的抑制作用逆转

Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis.

作者信息

van Amelsfort Jocea M R, van Roon Joel A G, Noordegraaf Madelon, Jacobs Kim M G, Bijlsma Johannes W J, Lafeber Floris P J G, Taams Leonie S

机构信息

University Medical Center Utrecht, Utrecht, The Netherlands.

出版信息

Arthritis Rheum. 2007 Mar;56(3):732-42. doi: 10.1002/art.22414.

DOI:10.1002/art.22414

PMID:17328044

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.

摘要

目的

我们之前证明，类风湿关节炎（RA）患者滑液（SF）中CD4⁺、CD25⁺调节性T（Treg）细胞数量增加，且与外周血（PB）中的对应细胞相比，其抑制活性增强。尽管RA中存在这些免疫调节细胞，但慢性炎症仍持续存在。本研究的目的是调查与RA相关的特定促炎介质是否能消除CD4⁺、CD25⁺ Treg介导的抑制作用。

方法

通过流式细胞术确定单核细胞表型，采用酶联免疫吸附测定法检测细胞因子水平。从RA患者的PB和SF中通过磁性分选获得的CD4⁺、CD25⁻和CD4⁺、CD25⁺ T细胞，在单独培养或与抗CD3单克隆抗体（mAb）和自体抗原呈递细胞共培养时，分别在不存在或存在抗CD28 mAb或促炎细胞因子白细胞介素-6（IL-6）、肿瘤坏死因子α（TNFα）或IL-7的情况下进行刺激。

结果

与PB来源的单核细胞相比，RA患者SF中的单核细胞HLA II类分子、CD80、CD86和CD40的表达增加，表明其处于活化状态。模拟这种共刺激潜能的增加，在CD4⁺、CD25⁻和CD4⁺、CD25⁺ T细胞共培养物中添加抗CD28 mAb导致PB和SF中CD4⁺、CD25⁺ Treg介导的抑制作用均降低。此外，IL-7以及在有限程度上的TNFα（两者均由活化的单核细胞产生且在SF中检测到）消除了CD4⁺、CD25⁺ Treg介导的抑制作用。相比之下，IL-6不影响Treg介导的抑制作用。