Abstract
Regulatory T cells (Treg) play a key role in maintaining the balance of immune responses in human health and in disease. Treg come in many flavors and can utilize a variety of mechanisms to modulate immune responses. In cancer, inducible (i) or adaptive Treg expand, accumulate in tissues and peripheral blood of patients, and represent a functionally prominent component of CD4+ T lymphocytes. Phenotypically and functionally, iTreg are distinct from natural (n) Treg. A subset of iTreg expressing ectonucleotidases CD39 and CD73 is able to hydrolyze ATP to 5′-AMP and adenosine (ADO) and thus mediate suppression of those immune cells which express ADO receptors. iTreg can also produce prostaglandin E2 (PGE2). The mechanisms responsible for iTreg-mediated suppression involve binding of ADO and PGE2 produced by iTreg to their respective receptors expressed on T effector cells (Teff), leading to the up-regulation of adenylate cyclase and cAMP activities in Teff and to their functional inhibition. The potential for regulating these mechanisms by the use of pharmacologic inhibitors to relieve iTreg-mediated suppression in cancer suggests the development of therapeutic strategies targeting the ADO and PGE2 pathways.
Highlights
Regulatory T cells (Treg), a small subset of CD4+ T lymphocytes (∼5%) in the peripheral blood, maintain immune responses in balance and ensure that potentially dangerous excessive immune reactivity is prevented
In the presence of ARL67156, a selective CD39 antagonist, or αβ-methylene ADP, an inhibitor of CD73, Tr1-mediated suppression of proliferation of autologous CSFE-labeled CD4+CD25(−) responder T cells was significantly blocked, restoring the ability of these cells to proliferate or produce cytokines [22]. These in vitro data suggested that human Tr1 co-expressing CD39 and CD73 could produce immunosuppressive ADO and could exert strong suppressive effects on T effector cells (Teff) functions via engaging A2A receptors (A2AR), as ZM241865, a selective A2AR antagonist, reversed suppression mediated by Tr1 [22]
We have recently reported that a CD4+CD73+CD39(−) subset of T cells, most CD19+ B cells which are CD39+CD73+ and CD39+CD73+ exosomes isolated from the plasma of NC or cancer patients are all good ADO producers in the presence of exogenous ATP [23]
Summary
Regulatory T cells (Treg), a small subset of CD4+ T lymphocytes (∼5%) in the peripheral blood, maintain immune responses in balance and ensure that potentially dangerous excessive immune reactivity is prevented. It is clear that Treg accumulate in tumor tissues and the peripheral circulation of cancer patients [7, 8], the role these Treg play in tumor progression or regression has not been clear, and associations between the Treg frequency and disease outcome remain a subject of a considerable dispute [9]. This is a clinically relevant dispute, because if Treg promote cancer progression by interfering with anti-tumor immunity, they need to be muzzled. In situ studies of Treg based on expression of FOXP3 in paraffin sections or the CD4+CD25+ cell frequency in cryosections may not be entirely reliable, and concerns exist that variable results for the Treg frequency in various human tumors, for example, may be the result of methodological differences rather than actual differences www.frontiersin.org
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