Background/Purpose:

Regulatory T cells (Tregs) are important for the maintenance of self-tolerance and are implicated in the origin of autoimmunity. Despite enrichment of Tregs in joints of rheumatoid arthritis (RA) patients, local inflammation persists and becomes chronic. Recently, CD39 expression has been described on FOXP3+ Tregs and suggested to be a novel mechanism of Treg suppression by producing anti-inflammatory adenosine together with CD73. Interestingly the capacity of CD39+ Treg to suppress Th17 responses is impaired in multiple sclerosis. Whether this defect is a general feature found in autoimmune diseases is currently unknown. In this study, we first aimed to better characterize the CD39+ Treg compartment in blood and synovial fluids from RA patients. We then further addressed their capacity in suppressing T effector cell responses, especially Th17 responses.

Methods:

Multi-parameter flow cytometry was used to assess the ex vivo frequencies of FOXP3+CD39+ and FOXP3+CD39- Tregs in blood of healthy controls (n=11) and RA patients (n=15) as well as at the site of inflammation of RA (n=15) and spondylarthropathy patients (n=10). In addition, the differential suppressive capacity of synovial CD39+ and CD39- Tregs was investigated by conventional co-culture systems (n=6). Proliferation and cytokine secretion was measured by thymidine incorporation and luminex, respectively.

Results:

FOXP3+CD39+ Tregs were enriched at the site of inflammation (p=0.0007) whereas synovial FOXP3+CD73+ Tregs were reduced compared to the circulation (p<0.001). The same pattern for CD39 and CD73 expression was also seen for the total population of synovial CD4+ T cells, (p<0.0001). Furthermore, synovial CD25+CD39+ Tregs were able to suppress proliferation of T effector cells (p=0.0313) in contrast to their CD39- counterparts that proliferated instead (p=0.026). Finally, cytokine suppression was exerted by the CD25+CD39+ Treg subset (and not by CD39-) for many cytokines but not for IL-17A.

Conclusion:

Our data suggest that FOXP3+CD39- and FOXP3+CD39+ Tregs are distinct subsets with different functions as exemplified by synovial CD39- T cells that proliferate in vitro and secrete pro-inflammatory cytokines instead of suppressing them. CD39- Tregs could represent plastic Tregs that converted to IL-17 producers under inflammatory conditions. Furthermore, we demonstrate that, in synovial fluid, CD39+ Treg are impaired in suppressing IL-17A secretion, a cytokine that may contribute to disease pathogenesis. This finding could partly explain why accumulation of Tregs is seen at the site of inflammation without facilitating remission.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd25cd39-regulatory-t-cells-are-enriched-at-the-site-of-inflammation-of-patients-with-rheumatoid-arthritis-and-impaired-in-suppressing-il-17a-secretion/