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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.

SUBMITTER: Kinsey GR 

PROVIDER: S-EPMC3431416 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Autocrine adenosine signaling promotes regulatory T cell-mediated renal protection.

Kinsey Gilbert R GR   Huang Liping L   Jaworska Katarzyna K   Khutsishvili Konstantine K   Becker David A DA   Ye Hong H   Lobo Peter I PI   Okusa Mark D MD  

Journal of the American Society of Nephrology : JASN 20120726 9


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  ...[more]

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