CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression

Abstract

a b s t r a c tExtracellular ATP is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. However, extracellular adenosine acts as an immunoregulatory signal that modulates the function of several cellular components of the adaptive and innate immune response. Consequently, the balance between ATP and adenosine concentration is crucial in immune homeostasis. CD39 and CD73 are two ectonucleotidases that cooperate in the generation of extracellular adenosine through ATP hydrolysis, thus tilting the balance towards immunosuppressive microenvironments. Extracellular adenosine can prevent activation, proliferation, cytokine production and cytotoxicity in T cells through the stimulation of the A2A receptor; however, recent evidence has shown that adenosine may also affect other processes in T-cell biology. In this review, we discuss evidence that supports a role of CD73 and CD39 ectonucleotidases in controlling naive T-cell homeostasis and memory cell survival through adenosine production. Finally, we propose a novel hypothesis of a possible role of these ectonucleotidases and autocrine adenosine signaling in controlling T-cell differentiation.

Purinergic Signaling Receptors Expression on Peripheral T-Lymphocytes of Healthy Donors

“…И наоборот, экспрессия CD39 увеличива-ется при активации Т-клеток. Клетки центральной памяти и эффекторной памяти экспрессируют обе нуклеотидазы-CD39 и CD73 -на своей поверх-ностной мембране [23].…”

“…Аденозин, продуцируемый CD73, является медиатором формирования систе-мы, которая блокирует дифференцировку Т-кле-ток, что способствует более эффективному фор-мированию долгоживущих Т-клеток памяти [23]. С другой стороны, было показано, что «наивные» CD45RA+CD45R0-CD8+ Т-клетки, экспрессиру-ющие CD73, обладают низкой чувствительностью к активации in vitro при помощи анти-CD3 анти-тел, но при добавление в среду для культивирова-ния анти-CD73 антител, уровень пролиферативной активности клеток резко увеличивался [27].…”

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].…”

“…Extracellular ATP also promotes phagocyte chemotaxis and leads to damaged cell clearance, as beautifully revised by Corriden and Insel [8]. Accumulated extracellular ATP gradually suffers enzymatic hydrolysis into adenosine, which, in turn, is read as a Breporter of excessive tissue damage,^as shown by Bono et al [9] As such, adenosine signaling is interpreted as an anti-inflammatory stimulus, generally opposing the effects induced by ATP. Interestingly, ATP may also be released by immune cells upon activation [7] and promotes immunological response fine-tuning.…”

“…A1AR has high affinity for adenosine and is the most abundant adenosine receptor in the brain, where it modulates several adenosine-induced effects, such as neuronal excitability and synaptic transmission [9,10]. In addition, pulmonary [11], cardiac [12], hepatic [13], and renal [14] inflammatory models have been explored to demonstrate that A1AR signaling leads to anti-inflammatory effects.…”