Background/Purpose: Human regulatory T (Treg) cells play an indispensable role for the maintenance of self tolerance and immune homeostasis. Numerous studies dealt with Treg population in peripheral blood from RA patients (RAPB) with various conclusions regarding the frequency of circulating Treg cells. Most studies reported decreased or normal proportions of Treg cells, whereas some other groups reported an increase. On the other hand, the frequency of Treg cells in synovial fluid from RA patients (RASF) has been reported to be significantly higher than that in RAPB. In addition, Treg cells in RASF have been shown to have impaired suppressive function compared to those in RAPB. However, the cause of impaired function of Treg cells in RASF is unknown. A recent study has demonstrated that human Treg cells can be separated into three functionally unique subpopulations: CD45RA+Foxp3^low naïve Treg cells; CD45RA-Foxp3^high effector Treg cells, both of which have suppressive functions, and non-suppressive cytokine-secreting CD45RA-Foxp3^lownon-Treg cells. The purpose of this study is to determine the characteristics of Foxp3+ Treg cells in RAPB and RASF.

Methods: Synovial fluid and peripheral blood CD4+ T cells from RA patients were classified into different subsets based on the expression of CD45RA, CCR7, CD27, and CD28. The frequency of IFN-γ-, IL-17-, or TNF-α-producing cells, and of Foxp3- or RANKL-positive cells in each subset was analyzed by eight-color flow cytometry. CD4+Foxp3+ cells were further classified into three functionally distinct subsets based on the expression of CD45RA and Foxp3.

Results: The frequency of CD45RA−Foxp3^high effector Treg cells was significantly decreased in the peripheral blood CD4+ T cells from RA patients, compared to those from healthy controls. As a result of the decrease of effector Treg cells, more than half of the Foxp3+ Treg cells (60.5 ± 9.5%) were the CD45RA−Foxp3^low non-Treg cells in RAPB. Furthermore, the frequency of CD45RA−Foxp3^high effector Treg cells in the CD27+CD28+ central memory (T_CM) subset was significantly decreased in RA patients. In addition, the percentage of CD45RA+Foxp3^low naïve Treg cells was negatively correlated with DAS28-CRP. In RASF, the frequency of Foxp3+ cells in the CD27+CD28+ effector memory (T_EM) population was significantly increased in RASF, compared to that in RAPB. Most of the Foxp3+ cells in RASF were CD45RA-Foxp3^low non-Treg cells (81.7 ± 10.4%), and the frequency of non-Treg cells in RASF was significantly increased compared to that in RAPB. Furthermore, the non-Treg cells in CD27+CD28+ T_EM subset was significantly increased in RASF (RASF; 5.9 ± 4.0%, RAPB; 0.7 ± 0.5%). Collectively, increase in Foxp3+ cells in RASF was due to increased number of non-Treg cells which exist in CD27+CD28+ T_EM subset.

Conclusion: The decreased proportion of CD45RA−Foxp3^high effector Treg cells and the increased proportion of CD45RA-Foxp3^low non-Treg cells may have critical roles in the pathogenesis of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/foxp3-regulatory-t-cells-in-peripheral-blood-and-synovial-fluid-of-patients-with-ra-a-comparative-phenotypic-analysis/