Hypoxia-inducible Factor-2? Is Necessary To Limit NKT Cell Cytotoxicity In Renal Ischemia/Reperfusion Injury

CD4+ natural killer T(NKT) cell is the major early-acting cell type and a fundamental immune modulator in renal ischemia-reperfusion injury(IRI). Because lymphocytes are exposed to various oxygen tensions under physiopathological conditions, we hypothesize that hypoxia-inducible factors(HIF) play a role in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we employed Lck-Cre transgene mice to specifically disrupt HIF-2? in T/NKT cells and found that HIF-2? knockout led to up-regulated Fas ligand(FasL) expression on peripheral NKT cells, but not on conventional T cells. HIF-2? knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated renal IRI, which could be antagonized by in vivo NK1.1+ cell depletion or FasL blockade. Compared with wild-type NKT cells, HIF-2?–/– NKT cells adoptively transferred to Rag1 knockout mice elicited severer renal IRI, and these mice were not protected by CGS21680, an adenosine A2 A receptor(adora2a) agonist. Mechanistically, hypoxia-induced adora2 a expression in NKT cells, as well as adora2 a activation-induced cAMP production was HIF-2?-dependent. Hydrogen peroxide-induced FasL expression on thymic NKT cells was significantly attenuated by CGS21680 treatment, which, however, lost its effect in HIF-2?–/– NKT cells. Finally, CGS21680 andlipopolysaccharide(LPS), an inducer of HIF-2? in endothelium, synergistically reduced the renal IRI to a surprising extent, but this effect was absent in Mx1-Cre-induced overall HIF-2? knockout mice. Taken together, our results reveal a previously unrecognized hypoxia/HIF-2?/adora2 a axis which restricts NKT cell activation when confronted with oxidative stress and thus prevents against renal IRI.