Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression

Abstract

The study of T regulatory cells (T reg cells) has been limited by the lack of specific surface markers and an inability to define mechanisms of suppression. We show that the expression of CD39/ENTPD1 in concert with CD73/ecto-5′-nucleotidase distinguishes CD4+/CD25+/Foxp3+ T reg cells from other T cells. These ectoenzymes generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on T reg cells and the adenosine A2A receptor on activated T effector cells generates immunosuppressive loops, indicating roles in the inhibitory function of T reg cells. Consequently, T reg cells from Cd39-null mice show impaired suppressive properties in vitro and fail to block allograft rejection in vivo. We conclude that CD39 and CD73 are surface markers of T reg cells that impart a specific biochemical signature characterized by adenosine generation that has functional relevance for cellular immunoregulation.

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

“…We found that in steady state, POM‐1 treatment significantly reduced accumulation of CD45 + Lineage (Lin, CD3/B220/CD11c/CD11b/NK1.1) − CD90.2 + RORγt + ILC3s, but not activated IL‐22‐producing ILC3s, in the colon (Figure 2d, e and Supplementary figure 4). In addition, POM‐1 also decreased colonic IL‐22 + CD3 + T cells as well as Foxp3 + Tregs (Figure 2e–g), the latter was in agreement with previous findings showing that NTPDases (especially CD39) are critical for Treg development and function 11. Administration of DSS did not change the numbers of RORγt + ILC3s in the colon but increased colonic IL‐22 + ILC3s by ~4‐fold while colonic IL‐22 + CD3 + T cells were not changed by DSS (Figure 2d, e, h, i).…”

“…ILC3s) in addition to reported mechanisms via regulation of the adaptive immune system (e.g. Treg and Th17/Th1 cells) 11, 12, 13…”

“…Recent studies have highlighted that the metabolism of purine nucleotides by NTPDases has a direct role in modulation of regulatory T cells (Tregs) and interleukin (IL)‐17‐producing Th17 cell functions,11, 12, 13 both important in the genesis of pathogenic T‐cell responses that form the characteristic of IBD 14. Interestingly, a further subset of immune cells, group 3 innate lymphoid cells (ILC3s), has also been shown to play a major role in gut mucosal immunity and inflammation 15, 16, 17.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Another mechanism leading to suppression of T-cell mediated immune responses is excessive production of adenosine by the cell surface enzyme CD73 (ecto-5′-nucleotidase) [128,129]. CD73 is usually expressed on endothelial and epithelial cells [130], subsets of leukocytes [131] and Foxp3 + Tregs [128,129], but also on several cancer types [132,133].…”

“…CD73 is usually expressed on endothelial and epithelial cells [130], subsets of leukocytes [131] and Foxp3 + Tregs [128,129], but also on several cancer types [132,133]. CD73 acts in concert with CD39 (ecto-apyrase) to produce adenosine in a coordinated two-step enzymatic conversion.…”