Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Abstract

Natural killer T (NKT) cells are the major early-acting immune cell type and fundamental immune modulators in ischemia-reperfusion injury (IRI). Because lymphocytes are exposed to various oxygen tensions under pathophysiologic conditions, we hypothesize that hypoxia-inducible factors (HIFs) have roles in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we used Lck-Cre transgenic mice to specifically disrupt HIF-2a in T/NKT cells and found that HIF-2a knockout led to upregulated Fas ligand expression on peripheral NKT cells, but not on conventional T cells. HIF-2a knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated IRI, which could be mitigated by in vivo NK1.1 + cell depletion or Fas ligand blockade.Compared with wild-type NKT cells, HIF-2a 2/2 NKT cells adoptively transferred to Rag1-knockout mice elicited more severe renal injury, and these mice were not protected by CGS21680, an adenosine A2A receptor agonist. Mechanistically, hypoxia-induced expression of adenosine A2A receptor in NKT cells and CGS21680-induced cAMP production in thymocytes were HIF-2a-dependent. Hydrogen peroxide-induced Fas ligand expression on thymic wild-type NKT cells was significantly attenuated by CGS21680 treatment, but this effect was lost in HIF-2a 2/2 NKT cells. Finally, CGS21680 and LPS, an inducer of HIF-2a in endothelium, synergistically reduced renal IRI substantially, but this effect was absent in Mx1-Cre-induced global HIF-2a-knockout mice. Taken together, our results reveal a hypoxia/HIF-2a/adenosine A2A receptor axis that restricts NKT cell activation when confronted with oxidative stress and thus protects against renal IRI.

Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair

“…Increased production of HIF in myeloid and lymphoid cells influences the innate and adaptive immune response. T-cell activation and proliferation is reduced under hypoxic conditions [216]. A study of Zhang et al [217] revealed a hypoxia/HIF-2α/adenosine2A receptor axis to be responsible in reduction of NK T-cells activation and renal IRI upon I/R.…”

Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer

“…52 Using conditional HIF-2a knockout mice, Zhang et al 52 show that HIF-2 helps suppress these cells by downregulating their Fas-ligand expression while at the same time inducing their expression of Adenosine A2A receptors. Potential mechanisms to reverse hypoxia-induced suppression of NK and NK-T cells remain to be discovered; however, Sarkar et al 47 do provide evidence that hypoxia-induced NK dysfunction can be reversed by exogenous IL-2 treatment.…”

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…Little is known about the expression or function of HIF-2 in DCs. In NK cells, HIF-2 limits cellular cytotoxicity, indicating an antiinflammatory role (41). Therefore, HIFs play a key role in multiple aspects of innate immune cell development and function.…”