Adenosine in the Thymus

Abstract

Adenosine is an ancient extracellular signaling molecule that regulates various biological functions via activating four G-protein-coupled receptors, A₁, A_2A, A_2B, and A₃ adenosine receptors. As such, several studies have highlighted a role for adenosine signaling in affecting the T cell development in the thymus. Recent studies indicate that adenosine is produced in the context of apoptotic thymocyte clearance. This review critically discusses the involvement of adenosine and its receptors in the complex interplay that exists between the developing thymocytes and the thymic macrophages which engulf the apoptotic cells. This crosstalk contributes to the effective and immunologically silent removal of apoptotic thymocytes, as well as affects the TCR-driven T-cell selection processes.

Keywords: T cell selection; adenosine; apoptosis; efferocytosis; thymocyte.

FIGURE 1

Suggested crosstalk between developing thymocytes and engulfing macrophages in the thymus involving adenosine. Dying thymocytes release ATP via caspase-regulated pannexin channels. ATP is then fast degraded to AMP by cell surface ATP degrading enzymes of thymocytes and macrophages, and to adenosine by CD73 expressed on the macrophage cell surface. ADO acting on thymocyte adenosine A_2A receptors induces “death by neglect” alone or promotes the glucocorticoid-induced death of DP thymocytes. In addition, it interferes with the negative selection of thymocytes that have TCR specificities with intermediate affinity for self-antigens, thus promote positive selection. ADO is also required for the tTreg formation. In dying thymocytes ADO enhances the intracellular expression of TG2, an apoptosis-related protein that promotes fast recognition of apoptotic cells by macrophages. In macrophages ADO activates adenosine A_2A receptors, the expression of which is strongly induced following apoptotic cell uptake. The mechanism involves both hem oxygenase and the lipid sensing peroxisome proliferator activating receptor δand liver X receptor that are triggered by the fatty acid and oxysterol content of the engulfed apoptotic cells, respectively. A_2A adenosine receptor signaling in macrophages prevents neutrophil chemokine formation and might also contribute to the apoptotic cell lipid content-induced upregulation of cell surface TG2. TG2 in macrophages acts as a phagocyte coreceptor for the proper phagocytosis of apoptotic cells, and contributes to the activation of latent TGF-β, an anti-inflammatory cytokine released by the engulfing macrophages.