Natural Killer Cells Are Present in Rag1(−/−) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

Rag1(−/−) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1(−/−) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1(null)IL2rg(null) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1(−/−) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1(−/−) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1(−/−) were comparable in number and function to those in WT mice. Rag1(−/−) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1(−/−) controls. Our results indicate that NK cells from Rag1(−/−) mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12975-021-00923-3.