Regulation of lymphocyte function by adenosine

Abstract

Adenosine regulates the interaction between lymphocytes and the vasculature, and is important for controlling lymphocyte trafficking in response to tissue injury or infection. Adenosine can blunt the effects of T cell receptor activation primarily by activating adenosine A(2A) receptors and signaling via cyclic AMP and protein kinase A. Protein kinase A reduces proximal T cell receptor signaling by phosphorylation of C-terminal Src kinase, nuclear factor of activated T cells and cyclic AMP response element-binding protein. Protein kinase A activation can either enhance or inhibit the survival of T cells depending on the strength and duration of signaling. Inducible enzymes such as CD73 and CD39 regulate adenosine formation and degradation in vivo. The extravasation of lymphocytes through blood vessels is influenced by A(2A) receptors-mediated suppression of intercellular adhesion molecule 1 expression on lymphocytes and diminished production of interferon γ and interferon γ-inducible chemokines that are chemotactic to activated lymphocytes. Adenosine also decreases the barrier function of vascular endothelium by activating A(2B)Rs. In sum, adenosine signaling is influenced by tissue inflammation and injury through induction of receptors and enzymes and has generally inhibitory effects on lymphocyte migration into inflamed tissues due to protein kinase A-mediated effects on adhesion molecules, interferon γ production, and endothelial barrier function.

Figure 1. Cyclic AMP signaling inhibits TCR and CD28 signaling in lymphocytes

Cyclic AMP accumulates in T cells in the region of lipid rafts in response to TCR activation, and more globally in response to strong Gs-coupled A_2AR activation. Cyclic AMP inhibits proximal TCR signaling through a pathway involving activation of protein kinase A-1 (PKA-1) and C-terminal Src kinase (Csk) to inhibit lymphocyte-specific protein kinase (Lck) and to reduce recruitment to CD3 of zeta-chain-associated protein kinase 70 (zap-70). PKA-1 also phosphorylates (indicated by red dots) and inhibits NF-AT. NF-AT activation is reversed by the Ca²⁺-calmodulin-dependent phosphatase, calcineurin. TCR-induced accumulation of cAMP near lipid rafts is reduced upon CD28 stimulation due to the activation of phosphatidylinositol-3-kinase (PI3-K) to produce PIP3. This results in translocation from the cytosol to the lipid raft of a complex consisting of AKT, PDE4 and β-arrestin (β-arr) by binding of the plextrin homology (PH) domain of AKT to PIP3. PDE4 degrades cAMP to relieve inhibition of TCR signaling. Abbreviations: A_2AR, adenosine A_2A receptor; Ado, adenosine; Ino, inosine; ADA, adenosine deaminase; α_sβγ, subunits of the heterotrimeric G protein, Gs; AC, adenylyl cyclase; AKT, a serine/threonine-specific protein kinase, also known as protein kinase B; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PDE4, type 4 phosphodiesterase; MHC, major histocompatibility complex; Ag, antigen; RhoH, Ras Homolog, a small GTP hydrolyzing protein; AKAP, A kinase anchor protein; TCR, T cell receptor; LAT, linker for activation of T cells; PLC, phospholipase C; PKC, protein kinase C; CaM, calmodulin; NF-AT, nuclear factor of activated T cells; CREB, cAMP response element-binding protein.