Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo

Abstract

To evaluate the direct effect of adenosine on cytokine-polarized effector T cells, murine type 1 helper T cells (Th1) and type 1 cytotoxic T lymphocytes (Tc1) and Th2/ Tc2 cells were generated using an antigenpresenting cell ( IntroductionAdenosine, which is released from metabolically active cells and generated extracellularly by degradation of released adenosine triphosphate (ATP), is a potent biologic mediator that modulates numerous cell functions. Adenosine protects cells and tissues during inflammation and ischemia 1,2 and mediates its effects via 4 receptor subtypes: the A 1 , A 2A , A 2B , and A 3 adenosine receptors. 2 G protein-coupled adenosine receptors are emerging as potential therapeutic targets, particularly for cardiac ischemia and neurodegenerative diseases. [1][2][3] Importantly, recent work indicates that regulation of inflammation through A 2A receptor signaling cannot be compensated by other pathways. Inflammatory cell damage causes adenosine to accumulate in tissues, which subsequently initiates a negative feedback signal in monocytes, neutrophils, and lymphocytes via the A 2A receptor. 3 Therefore, adenosine is believed to "put the brake on inflammation." 4 Immunosuppression through adenosine A 2A receptor activation of T lymphocytes has been previously documented. 5,6 However, these studies were performed with naive T cells under initial stimulation conditions; therefore, little is known regarding A 2A receptor activation of polarized effector T-cell populations. This question is of significant interest, as tissue damage and subsequent adenosine accumulation likely occurs relatively late in the inflammatory process, after T-cell maturation and differentiation. Therefore, it is possible that mature T cells may be a more relevant target of A 2A stimulation than naive T cells.Furthermore, depending on the cytokine environment during initial antigen encounter, T cells can differentiate either into type 1 T cells that secrete primarily interleukin 2 (IL-2) and interferon ␥ (IFN-␥) or type 2 T cells that secrete primarily IL-4, IL-5, and IL-10. This type 1/type 2 cytokine polarization exists for both CD4 ϩ T cells (Th1/Th2 subsets) and for CD8 ϩ T cells (Tc1/Tc2 subsets). Importantly, Th1/Th2 and Tc1/Tc2 states of T-cell differentiation appear to influence disease pathogenesis, especially inflammatory processes. 7 Because Tc1 and Tc2 subsets of CD8 ϩ T cells each can mediate potent target cell lysis and secrete cytokines that exert differential effects on inflammation, we hypothesized that adenosine receptors, and in particular, those of the A 2A subtype, may operate differentially in these immune effector subsets. Materials and methods MiceFemale, 6-to 8-week-old (C57Bl/6 x Balb/c)F 1 (CB6F 1 , H-2K b/d ), C57Bl/6 (H-2K b ), and congenic C57Bl/6 Ly5.1 mice were obtained from the Frederick Cancer Research Facility (FCRF, Frederick, MD) and maintained in a specific pathogen-free facility. All experiments were performed according to an animal protocol approved by the National Cancer Institute (...

Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression

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“…Like CBD, adenosine receptor agonists and uptake inhibitors decrease serum TNF␣ in LPS-treated mice (13). In addition, THC and adenosine each have the ability to suppress the T helper 1 response while enhancing the T helper 2 response (14,15).…”

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

“…Adenosine receptors (ARs) are also found on cells of the immune system and have been recognized to play an important role in inflammatory conditions [4][5][6][7], in which adenosine can act as an antiinflammatory and immunosuppressive mediator mainly via the activation of A 2A receptors. It inhibits TNF-α production and has been implicated as a physiological signal in the apoptotic deletion of T cells during intrathymic cell selection, a process which functions to prevent autoimmunity [8][9][10][11].…”

Foxp3-dependent programme of regulatory T-cell differentiation

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