Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

• Published in: Purinergic signalling Vol. 15; no. 2; pp. 127 - 137
• Main Authors: Woehrle, Tobias, Ledderose, Carola, Rink, Jessica, Slubowski, Christian, Junger, Wolfgang G.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.06.2019; Springer Nature B.V
• Subjects: Autocrine Communication; Autocrine signalling; Biomedical and Life Sciences; Biomedicine; Calcium (mitochondrial); Calcium influx; Calcium signalling; Cancer Research; CD28 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Cells, Cultured; Human Physiology; Humans; Interleukin 2; Lymphocyte Activation - physiology; Lymphocytes; Lymphocytes T; Mitochondria; Neurosciences; Original; Original Article; Pharmacology/Toxicology; Purine P2X receptors; Receptor mechanisms; Receptors, Purinergic P2X - metabolism; Receptors, Purinergic P2Y1 - metabolism; Signal Transduction - immunology; T cell receptors; Therapeutic applications; Transcription; T lymphocytes; Cell activation; Immune cells; Purinergic signaling
• ISSN: 1573-9538; 1573-9546
• DOI: 10.1007/s11302-019-09653-6

Previous studies have shown that T cell receptor (TCR) and CD28 coreceptor stimulation involves rapid ATP release, autocrine purinergic feedback via P2X receptors, and mitochondrial ATP synthesis that promote T cell activation. Here, we show that ADP formation and autocrine stimulation of P2Y1 receptors are also involved in these purinergic signaling mechanisms. Primary human CD4 T cells and the human Jurkat CD4 T cell line express P2Y1 receptors. The expression of this receptor increases following T cell stimulation. Inhibition of P2Y1 receptors impairs the activation of mitochondria, as assessed by mitochondrial Ca 2+ uptake, and reduces cytosolic Ca 2+ signaling in response to TCR/CD28 stimulation. We found that the addition of exogenous ADP or overexpression of P2Y1 receptors significantly increased IL-2 mRNA transcription in response to TCR/CD28 stimulation. Conversely, antagonists or silencing of P2Y1 receptors reduced IL-2 mRNA transcription and attenuated T cell functions. We conclude that P2Y1 and P2X receptors have non-redundant, synergistic functions in the regulation of T cell activation. P2Y1 receptors may represent potential therapeutic targets to modulate T cell function in inflammation and host defense.