title: Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection.
abstract: Regulatory T cells (Tregs) suppress the innate inflammation associated with kidney ischemia-reperfusion injury (IRI), but the mechanism is not well understood. Tregs express CD73, the final enzyme involved in the production of extracellular adenosine, and activation of the adenosine 2A receptor (A(2A)R) on immune cells suppresses inflammation and preserves kidney function after IRI. We hypothesized that Treg-generated adenosine is required to block innate immune responses in kidney IRI and that the Treg-generated adenosine would signal through A(2A)Rs on inflammatory cells and, in an autocrine manner, on Tregs themselves. We found that adoptively transferred wild-type Tregs protected wild-type mice from kidney IRI, but the absence of adenosine generation (CD73-deficient Tregs) or adenosine responsiveness (A(2A)R-deficient Tregs) led to inhibition of Treg function. Pharmacologic stimulation of A(2A)R before adoptive transfer augmented the ability of wild-type and CD73-deficient Tregs to suppress kidney IRI. Microarray analysis and flow cytometry revealed that A(2A)R activation enhanced surface PD-1 expression on Tregs in the absence of any other activation signal. Treatment of Tregs with a PD-1 blocking antibody before adoptive transfer reversed their protective effects, even if pretreated with an A(2A)R agonist. Taken together, these results demonstrate that the simultaneous ability to generate and respond to adenosine is required for Tregs to suppress innate immune responses in IRI through a PD-1-dependent mechanism.
authors: Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia Health System, Box 800746, Charlottesville, VA 22908, USA. grk4n@virginia.edu
authors: Gilbert R
authors: GR
authors: Kinsey
authors: Liping
authors: L
authors: Huang
authors: Katarzyna
authors: K
authors: Jaworska
authors: Konstantine
authors: K
authors: Khutsishvili
authors: David A
authors: DA
authors: Becker
authors: Hong
authors: H
authors: Ye
authors: Peter I
authors: PI
authors: Lobo
authors: Mark D
authors: MD
authors: Okusa
mesh_terms: D015720:5'-Nucleotidase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000241:Adenosine / Q000502:physiology*; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000473:pathology / Q000502:physiology*
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D043705:Receptor, Adenosine A2A; D015720:5'-Nucleotidase; D000241:Adenosine