Innate lymphoid cells (ILCs) are innate counterparts of adaptive T lymphocytes, contributing to host defense, tissue repair, metabolic homeostasis, and inflammatory diseases. ILCs have been considered to be tissue-resident cells, but whether ILCs move between tissue sites during infection has been unclear. We show here that interleukin-25- or helminth-induced inflammatory ILC2s are circulating cells that arise from resting ILC2s residing in intestinal lamina propria. They migrate to diverse tissues based on sphingosine 1-phosphate (S1P)-mediated chemotaxis that promotes lymphatic entry, blood circulation, and accumulation in peripheral sites, including the lung, where they contribute to anti-helminth defense and tissue repair. This ILC2 expansion and migration is a behavioral parallel to the antigen-driven proliferation and migration of adaptive lymphocytes to effector sites and indicates that ILCs complement adaptive immunity by providing both local and distant tissue protection during infection.

Members of the N-methyl-D-aspartate (NMDA) class of glutamate receptors (NMDARs) are critical for development, synaptic transmission, learning and memory; they are targets of pathological disorders in the central nervous system. NMDARs are phosphorylated by both serine͞threonine and tyrosine kinases. Here, we demonstrate that cyclin dependent kinase-5 (Cdk5) associates with and phosphorylates NR2A subunits at Ser-1232 in vitro and in intact cells. Moreover, we show that roscovitine, a selective Cdk5 inhibitor, blocks both long-term potentiation induction and NMDAevoked currents in rat CA1 hippocampal neurons. These results suggest that Cdk5 plays a key role in synaptic transmission and plasticity through its up-regulation of NMDARs. The N-methyl-D-aspartate (NMDA) class of glutamate receptors (NMDAR) are essential for learning, memory, and development in the central nervous system (1-5). NMDARs are multimeric complexes formed from both NMDA receptor subunit (NR1) and modulatory NR2 subunits (6-9). A single gene encodes the NR1 subunit. Eight possible alternative RNA-splice variants provide molecular diversity of NMDARs (10). NR2A-NR2D are encoded by four separate genes (11,12). NMDARs consist of NR1͞NR2 heteromeric complexes (13-15). The activation of NMDARs and the influx of Ca NMDA-channel activity is dynamically modulated in both intracellular and extracellular sites (3). Phosphorylation sites have been identified on the NR1, NR2A, and NR2B subunits, but not on the NR2C-NR2D subunits. Protein kinase C phosphorylates Ser-890 and Ser-896, and protein kinase A phosphorylates Ser-897 within the C1 exon of the NR1 subunit (17-19). Calcium͞calmodulin protein kinase II mediates phosphorylation of NR2B, but not NR2A (20). More recently, phosphorylation at tyrosine residues of NR2A and NR2B has been described as an important determinant for NMDAR functions (19)(20). In particular, Fyn, a member of the Src family of nonreceptor protein tyrosine kinases, was shown to phosphorylate the NR2A (7, 21-23). However, no information is available concerning which kinases phosphorylate NR2A at serine͞threonine sites. Cyclindependent kinase-5 (Cdk5) is a serine͞threonine kinase that is activated by neuron-specific p35 and p39 proteins (24-27). It exists as a large, multimeric complex associated with cytoskeletal proteins in the neurons. Cdk5 has been shown to phosphorylate a wide variety of proteins, all of which have serine͞threonine sites in (K͞RT͞SPXK)-type motifs (28,29). A number of synaptic proteins have been identified as Cdk5 substrates (30-32). Cdk5 and p35, predominantly expressed in postmitotic neurons, play essential roles in neuronal migration, neurite outgrowth, and laminar configuration of the cerebral cortex (25,27,33). Cdk5 in association with p25, a truncated form of p35, hyperphosphorylates the microtubule-associated protein tau. This hyperphosphorylation is thought to disrupt the neuronal cytoskeleton and ultimately contributes to neurodegeneration in Alzheimer's disease (34).Because of its virtue of phosphoryl...