CD39 and T-cells
Within the T-cell population, CD39 is mainly expressed by CD4+ lymphocytes and mainly by regulatory T-cell (Treg) subsets [25]. The expression of CD39 in CD4+ T-cells increases with age and CD39+CD4+ T-cells were found to be prone to apoptosis and metabolic stress [26]. Both CD39 and CD73 are expressed in Tregs and hydrolyze pericellular ATP into ADO, which contributes to Treg immune suppressive functions[27, 28]. Previous reports indicated that 90% of human Foxp3+Tregs are CD39+[25, 29]. Initial phenotypic and functional analyses demonstrated that CD4+CD25highCD39+CD45RO+cells had properties consistent with effector Treg, CD4+CD25highCD39CD45ROcells were naïve Tregs, and CD4+CD25highCD39CD45RO+cells were predominantly non-Tregs with effector T-cell functions[30]. CD39+Treg cells demonstrated more potent suppressive abilities compared to conventional Treg cells. Tregs induced by CD39+ naïve T-cells, CD39+ iTregs, demonstrate enhanced proliferation and suppressive abilities [31]. CD8+iTregs displayed increased CD39 expression in patients with systemic lupus erythematosus (SLE) nephritis, which was shown to play an important role in the suppressive function of human CD8+ iTregs [32]. CD39high Tregs were more stable and functional than CD39low Tregs. Cultured CD39highTregs maintained stable forkhead box protein 3 (Foxp3) expression, whereas CD39low Tregs lost Foxp3 expression and trans-differentiated into Th1 or Th17 cells. Furthermore, human CD4+CD39high Tregs, but not CD4+CD39low Tregs, protected against xenograft-versus-host-disease in mice models [33]. Mouse Tregs showed increased CD39 activity only when their T-cell receptor (TCR) was activated, while the CD39 enzyme was found to be ineffective in unstimulated cells [34]. CD39 is also highly expressed in tumor-infiltrating Tregs and participates in Tregs-mediated immunosuppression [35-37]. Some CD4+ T cells do not express FoxP3, but express CD39[25, 38]. These T-cells have a unique phenotype called the memory effect, and they have no immunosuppressive capacities.
CD39 is also expressed in CD8+ cells. It was reported to be highly expressed in a variety of human tumor-infiltrating CD8+ T-cells found in renal cancer, gastric cancer[39], lung cancer, colorectal cancer, breast cancer [40] and head and neck cancer[41]. Tumor-infiltrating CD39highCD8+ T-cells increase with tumor growth and exhibit features of exhaustion[40]. CD39+CD8+Tc1 cells limit interferon-γ (IFN-γ) production of CD39-CD8+ T-cells by generating ADO, which acts in a paracrine manner [42].
CD39 is expressed on Th17 cells, and co-expression of CD39 and CD161 by CD4+ T-cells might serve as a biomarker to monitor Th17 responsiveness [43]. The expression of CD39 and CD73 on the surface of Th17 cells is closely regulated by IL-6 and TGF-β, which induce Th17 differentiation [44]. Furthermore, CD39 activity regulates the conversion of Th17 cells into IL-10-producing cells in vitro , which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156[45]. In a mouse cancer model, Th17 cells produced in the presence of TGF-β were shown to have high expression levels of CD39 and CD73, which inhibit T-cell response and promote tumor growth in an ADO-dependent manner [44]. Moreover, CD39+ Th17 cells in juvenile autoimmune liver disease (AILD) are both quantitatively decreased and qualitatively deficient. Low expression levels of CD39 and A2AR may contribute to the perpetuation of Th17 cell effector properties and unfettered inflammation in this disease [46].
CD39 is also expressed in other types of T cells. Tissue-resident memory T-cells (Trm) express high levels of PD-1, TIGIT, and CD39 and represent tumor-reactive tumor-infiltrating lymphocytes[47]. CD39 has been reported as a surface marker of mouse regulatory γδT-cells, which have been shown to suppress contact hypersensitivity [48].