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Renal Ischemia-Reperfusion Injury and Adenosine 2A Receptor-Mediated Tissue Protection: The Role of CD4⁺ T Cells and IFN-¹

Yuan-Ji Day^2,*, Liping Huang^*, Hong Ye^*, Li Li^*, Joel Linden^*, and Mark D. Okusa^3,*,

^* Department of Medicine and Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908

A_2A adenosine receptor (A_2AR)-expressing bone marrow (BM)-derived cells contribute to the renal protective effect of A_2A agonists in renal ischemia-reperfusion injury (IRI). We performed IRI in mice lacking T and B cells to determine whether A_2AR expressed in CD4⁺ cells mediate protection from IRI. Rag-1 knockout (KO) mice were protected in comparison to wild-type (WT) mice when subjected to IRI. ATL146e, a selective A_2A agonist, did not confer additional protection. IFN- is an important early signal in IRI and is thought to contribute to reperfusion injury. Because IFN- is produced by kidney cells and T cells we performed IRI in BM chimeras in which the BM of WT mice was reconstituted with BM from IFN- KO mice (IFN- KOWT chimera). We observed marked reduction in IRI in comparison to WTWT chimeras providing additional indirect support for the role of T cells. To confirm the role of CD4⁺ A_2AR in mediating protection from IRI, Rag-1 KO mice were subjected to ischemia-reperfusion. The protection observed in Rag-1 KO mice was reversed in Rag-1 KO mice that were adoptively transferred WT CD4⁺ cells (WT CD4⁺Rag-1 KO) or A_2A KO CD4⁺ cells (A_2A KO CD4⁺Rag-1 KO). ATL146e reduced injury in WT CD4⁺Rag-1 KO mice but not in A_2A KO CD4⁺Rag-1 KO mice. Rag-1 KO mice reconstituted with CD4⁺ cells derived from IFN- KO mice (IFN- CD4⁺Rag-1 KO) were protected from IRI; ATL146e conferred no additional protection. These studies demonstrate that CD4⁺ IFN- contributes to IRI and that A_2A agonists mediate protection from IRI through action on CD4⁺ cells.

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