Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions

Abstract

Autoimmune diseases are characterized by an imbalance between regulatory T cells and effector T-cell subsets, such as Th1 and Th17 cells. Studies have confirmed that natural CD4+Foxp3+ Tregs were unstable and dysfunctional in the presence of pro-inflammatory cytokines. In the current study, human CD39hi Tregs and CD39low Tregs were sorted from Tregs in vitro after 7 days of expansion. The functions of both Treg subsets were investigated under inflammatory conditions in vitro and in vivo. In the presence of IL-1β and IL-6, cultured CD4+CD39hi Tregs maintained stable forkhead box protein 3 expression, whereas CD4+CD39low Tregs lost Foxp3 expression and trans-differentiated into Th1 or Th17 cells. Decreased IL-1βR and IL-6R expression on the CD39hi Tregs was the primary mechanism responsible for Treg stability. In addition, reduced activation of downstream molecules, such as STAT1 and STAT3, through the modulation of CpG demethylation played an important role. Finally, human CD4+CD39hi Tregs but not CD4+CD39low Tregs protected against xenograft versus host disease in model mice. These results strongly implied the physiological importance of CD39 expression and suggested that manipulation of CD39hi Tregs might represent a novel strategy for the treatment of autoimmune diseases.

CTLA-4+PD-1− Memory CD4+ T Cells Critically Contribute to Viral Persistence in Antiretroviral Therapy-Suppressed, SIV-Infected Rhesus Macaques

“…Even when gating on CD25 + CD127 − cells, we found a significant enrichment in CTLA-4 + PD-1 − CD4 + T cells as compared to the PD-1 + CTLA-4 − and PD-1 − CTLA-4 − subsets, for several markers previously shown to be expressed on subsets of Tregs and to promote Treg cell stability and suppressive activity. These markers include latency associated peptide (Chen et al, 2008); the transcription factor Helios (Baine et al, 2013; Ross et al, 2014); the plasma membrane protein CD39 (Borsellino et al, 2007; Gu et al, 2017); and the chemokine receptor CCR6 (Kitamura et al, 2010; Xu et al, 2010) (Figure S6A,B; p<0.001 for all markers). Thus, CTLA-4 + PD-1 − memory CD4 + T cells include functional Treg cells and represent a subset that contributes to SIV persistence during ART in multiple anatomic sites.…”

Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis

“…CD39 is a member of the ectonucleoside triphosphate diphosphohydrolase family, which has been shown to hydrolyze pro‐inflammatory adenosine triphosphate (ATP) to adenosine diphosphate and finally adenosine, which inhibits cytotoxic lymphocyte activation and reduces production of pro‐inflammatory cytokines upon activation of the adenosine A2A receptor . CD39 stabilizes the suppressor phenotype of Tregs under inflammatory conditions and enhances their suppressor activity . There is emerging evidence that CD39+ CD4+ cells prevent ischemia reperfusion inflammatory liver injury, promote liver allograft tolerance in mice, and have profound effects on antitumor immune surveillance in the liver …”

OMIP‐053: Identification, Classification, and Isolation of Major FoxP3 Expressing Human CD4+ Treg Subsets

“…The panel enables the further characterization of TDP in terms of the following properties: (i) Activation status (CD38, HLA‐DR), (ii) Naïve/memory phenotype/antigen‐experienced/inexperienced (CCR7, CD45RA), (iii) ontogeny (presumably thymic versus induced: HELIOS, TIGIT/CD226), (iv) suppressive capacity and stability (CD39) , and (v) proliferation (Ki67). Ki67 was considered essential given its usefulness in delineating activated Treg populations which may be of prognostic value in malignant disease .…”