Central nervous system (CNS)–resident natural killer cells suppress Th17 responses and CNS autoimmune pathology

Abstract

Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention.

Ischemic neurons recruit natural killer cells that accelerate brain infarction

“…The present finding that NK cells promoted inflammation and neuronal damage in stroke indicated distinctive activity of NK cells during experimental autoimmune encephalomyelitis (EAE) (16,25), a mouse model of human multiple sclerosis. In EAE, NK cells, together with myelin-reactive T cells, are activated in the periphery before they migrate to the brain.…”

“…NK1.1 + cells (NK and NKT cells) can be efficiently depleted with anti-NK1.1 mAb, as previously reported (16). WT mice treated with isotype IgG served as controls.…”

“…2C) of MCAO mice. Next, NK cell chemotaxis to CX3CL1 was confirmed in vitro by coculture of cortical neurons and NK cells in a transwell migration assay (16). Cultured cortical neurons were subjected to hypoxic conditions by combined oxygen-glucose deprivation (OGD) for 60 min, a condition that mimics ischemia in vivo.…”

“…To define the time window during which NK cells exert their impact on stroke, we administered anti-NK1.1 mAb to deplete NK cells (16) or isotype control IgG to groups of mice at 6, 12, and 24 h after MCAO. We found that NK cell depletion at 6 h after MCAO attenuated neurological deficits and infarct volume (Fig.…”

“…We , and 24 h after reperfusion, respectively. Treatment regimen and efficiency of cell depletion are described elsewhere (16,30). Neurological deficits (D and F) were assessed, and infarct volumes (E and G) were determined by MRI in conjunction with TTC staining.…”