Extracellular Adenosine-Mediated Modulation of Regulatory T Cells

Abstract

Extracellular adenosine-dependent suppression and redirection of pro-inflammatory activities are mediated by the signaling through adenosine receptors on the surface of most immune cells. The immunosuppression by endogenously-produced adenosine is pathophysiologically significant since inactivation of A2A/A2B adenosine receptor (A2AR/A2BR) and adenosine-producing ecto-enzymes CD39/CD73 results in the higher intensity of immune response and exaggeration of inflammatory damage. Regulatory T cells (Treg) can generate extracellular adenosine, which is implicated in the immunoregulatory activity of Tregs. Interestingly, adenosine has been shown to increase the numbers of Tregs and further promotes their immunoregulatory activity. A2AR-deficiency in Tregs reduces their immunosuppressive efficacy in vivo. Thus, adenosine is not only directly and instantly inhibiting to the immune response through interaction with A2AR/A2BR on the effector cells, but also adenosine signaling can recruit other immunoregulatory mechanisms, including Tregs. Such interaction between adenosine and Tregs suggests the presence of a positive feedback mechanism, which further promotes negative regulation of immune system through the establishment of immunosuppressive microenvironment.

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

“…The dramatic increase in A2A expression under low O 2 tension (supplemental Figure 8C) suggested that inhibition of T-cell proliferation was obtained through the adenosinergic axis, as shown previoulsy. 49 Consistently, ligation of the A2A under hypoxia further decreased T-cell proliferation, while the SCH58261 antagonist partially rescued it ( Figure 6A; supplemental Figure 8B). …”

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

“…This finding is in line with the emerging data which indicate that inhibitory and stimulatory signals are handled differently in regulatory lymphocytes such as Treg vs. Teff lymphocytes. 9 For example, usually inhibitory signaling via PD-1 is reported altered to stimulatory signaling in Treg found in environments rich in suppressive factors such as tumor microenvironments. 33,34 Our data suggest that the same mechanisms of "reverse" signaling apply to Breg.…”

“…6,7 In contrast, peripheral regulatory T cells (pTreg) or myeloid-derived suppressor cells (MDSC) are activated by ADO signaling via A 2A R and their immunosuppressive functions are enhanced. 8,9 The role of A 1 R or A 3 R in ADO-mediated immune regulation is not entirely clear, although 5 0 -AMP was reported to be an A 1 R agonist with affinity equal to or better than that of ADO. 10 In cancer, ADO is viewed as a pro-tumor factor which suppresses antitumor functions of Teff and promotes functions of suppressor cells (Treg and MDSC).…”

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

“…Such mechanism, initially suggested by the correlation between adenosine deaminase and immunodeficiency in 1975 [171], was gradually confirmed in the cancer context [9,172,173] and also as a strategy used by Tregs [9,174].…”