Abstract
Innate lymphoid cells (ILCs) are tissue resident cells with organ-specific properties. Here, we show that the central nervous system (CNS) encompasses ILCs. In particular, CD3−NK1.1+ cells present in the murine CNS comprise natural killer (NK) cells, ILC1s, intermediate ILC1s (intILC1s) and ex-ILC3s. We investigated the properties of CNS-ILC1s in comparison with CNS-NK cells during steady state and experimental autoimmune encephalomyelitis (EAE). ILC1s characteristically express CXCR3, CXCR6, DNAM-1, TRAIL, and CD200R and display heightened TNF-α production upon stimulation. In addition, ILC1s express perforin and are able to degranulate, although in a lesser extent than NK cells. Within the CNS compartments, ILC1s are enriched in the choroid plexus where very few NK cells are present, and also reside in the brain parenchyma and meninges. During EAE, ILC1s maintain stable IFN-γ and TNF-α levels while in NK cells the production of these cytokines increases as EAE progresses. Moreover, the amount of ILC1s and intILC1s increase in the parenchyma during EAE, but in contrast to NK cells, they show no signs of local proliferation. The upregulation in the inflamed brain of chemokines involved in ILC1 migration, such as CXCL9, CXCL10, and CXCL16 may lead to a recruitment of ILC1s from meninges or choroid plexus into the brain parenchyma. In sum, CNS-ILC1 phenotype, distribution and moderate inflammatory response during EAE suggest that they may act as gatekeepers involved in the control of neuroinflammation.
Highlights
Innate lymphoid cells (ILCs) are tissue resident cells [1] that contribute to tissue homeostasis and react early to local inflammatory events [reviewed in [2]]
natural killer (NK) cells were defined in the mouse as CD3-negative cells that express the natural cytotoxicity receptor (NCR) NKp46 and NK1.1 [8,9,10]; receptors that are expressed on ILC1s and a subset of ILC3s [5, 11]
We identified immature CD27+ NK cells in both, healthy and inflamed mouse central nervous system (CNS)
Summary
Innate lymphoid cells (ILCs) are tissue resident cells [1] that contribute to tissue homeostasis and react early to local inflammatory events [reviewed in [2]]. The long-known conventional natural killer (NK) cells are categorized as cytotoxic ILCs, which share phenotypical and functional similitudes with helper-like ILC1s [3]. Properties of CNS Group 1 ILCs different precursor cells [4, 5], both express the T-box family transcription factor T-bet and secrete type I cytokines, such as interferon-γ (IFN-γ). Apart from to T-bet, NK cells express and depend on the transcription factor Eomesodermin (Eomes) for their development [6, 7]. While CD3−NK1.1+/NKp46+ circulating or splenic NK cells express the α2 integrin CD49b (DX5 antigen) [12], ILC1s express the α1 or αE forms (CD49a and CD103, respectively), and the lectin CD69, which contribute to cell retention into the tissues [13,14,15]
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