Abstract 17343: Innate T Cells Improve Brain Injury and Mortality After Cardiac Arrest and Resuscitation

Abstract

Introduction: Systemic inflammation may contribute to brain injury and mortality after cardiac arrest and resuscitation (CA/CPR). The early increase of inflammatory cytokines (such as interferon-γ [IFNγ]) suggests a role for innate immunity in CA/CPR. Natural Killer T (NKT) cells, a type of innate T cell, are “master regulators” of IFNγ and other facets of the early innate immune response in other disease models. To study the regulation of innate immunity after CA/CPR, we examined CD1dKO mice (which lack both invariant NKT cells and diverse NKT cells) and Jα18 KO mice (which lack only invariant NKT cells). Hypothesis: NKT cells control inflammation, brain injury, and mortality in CA/CPR. Methods: Mice were mechanically ventilated, underwent 8 min. of normothermic CA with potassium chloride i.v. and were resuscitated with chest compressions and epinephrine i.v. Results: Surprisingly, normally pro-inflammatory NKT cells had a protective effect. After CA/CPR, pan-NKT cell-deficient (CD1d KO) mice had markedly worsened brain injury and mortality compared to wild-type (WT) mice; but Jα18 KO mice (which only lack invariant NKT cells) had similar outcomes as WT mice. These results suggested that diverse NKT cells had a protective role after CA/CPR. Pan-NKT cell-deficient (CD1d KO) mice had exaggerated IFNγ production by NK and innate lymphoid cells (ILC1s) after CA/CPR. In line with the increased IFNγ and worsened outcomes in NKT cell-deficient mice, IFNγ-deficient (IFNγ KO) mice had improved brain injury and mortality after CA/CPR, compared to WT mice. Finally, NKT cell-deficient mice were rescued by IFNγ deficiency (Cd1d-/- Ifng-/- double KO mice). Conclusions: Unexpectedly, diverse NKT cells were anti-inflammatory and protective in CA/CPR. In CA/CPR, diverse NKT cells reduced IFNγ levels, and reduction of IFNγ improved mortality and brain injury. Innate T cells and IFNγ may be targets for therapeutic intervention in CA/CPR.