ABSTRACT:Glioblastoma (

NK cells are important players in immunity against pathogens and neoplasms. As a component of the innate immune system, they are one of the first effectors on sites of inflammation. Through their cytokine production capacities, NK cells participate in the development of a potent adaptive immune response. Furthermore, NK cells were found to have regulatory functions to limit and prevent autoimmunity via killing of autologous immune cells. These paradoxical functions of NK cells are reflected in CNS disorders. In this review, we discuss the phenotypes and functional features of peripheral and brain NK cells in brain tumors and infections, neurodegenerative diseases, acute vascular and traumatic damage, as well as mental disorders. We also discuss the implication of NK cells in neurotoxicity and neuroprotection following CNS pathology, as well as the crosstalk between NK cells and brain-resident immune cells.

Hematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3–adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes.

NK cells are lymphocytes of the innate immune system which are a first line of defense against infections and tumor cells, in bone marrow and peripheral organs like lung and spleen. The lung is an organ in contact with respiratory pathogens and the site of inflammatory disorders triggered by the respiratory environment. In contrast, spleen is a lymphatic organ connected to the blood system which regulates the systemic immune response. Here we compare NK cell maturation and expansion as well as expression of NK cell receptors in spleen and lung compartments. We show that spleen and lung NK cells differ in phenotypic and functional characteristics due to a difference of maturity and cellular microenvironment. Indeed we observe that spleen and lung macrophages have the capacity to influence the cytotoxicity of NK cells by cell-to-cell contact. This suggests that the differences of NK cell subsets are in part due to a modulation by the organ environment.

38 Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme into the tricarboxylic acid (TCA) cycle. Here we show that 39 PARK7/DJ-1, a key familial Parkinson's disease (PD) gene, is a pacemaker controlling PDH activity in CD4 regulatory 40 T cells (Tregs). DJ-1 bound to PDH-E1 beta (PDHB), inhibiting the phosphorylation of PDH-E1 alpha (PDHA), thus 41 promoting PDH activity and oxidative phosphorylation (OXPHOS). Dj-1 depletion impaired Treg proliferation and 42 cellularity maintenance in older mice, increasing the severity during the remission phase of experimental autoimmune 43 encephalomyelitis (EAE). The compromised proliferation and differentiation of Tregs in Dj-1 knockout mice were caused 44 via regulating PDH activity. These findings provide novel insight into the already complicated regulatory machinery of 45 the PDH complex and demonstrate that the DJ-1-PDHB axis represents a potent target to maintain Treg homeostasis, 46 which is dysregulated in many complex diseases. 47 48 9 Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset 789 parkinsonism. Science 299, 256-259, 792 11 van der Brug, M. P. et al. RNA binding activity of the recessive parkinsonism protein DJ-1 supports 793 involvement in multiple cellular pathways.