Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation1. NK cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses2–4. NK cells mediate resistance against hematopoietic neoplasms but are generally considered to play a minor role in solid tumor carcinogenesis5–7. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis and cytomegalovirus infection.

In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1 G93A , we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43 A315T . NK cells are neurotoxic to hSOD1 G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3 + /Treg cell infiltration in the spinal cord of hSOD1 G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.

Mice exposed to standard (SE) or enriched environment (EE) were transplanted with murine or human glioma cells and differences in tumour development were evaluated. We report that EE exposure affects: (i) tumour size, increasing mice survival; (ii) glioma establishment, proliferation and invasion; (iii) microglia/macrophage (M/Mφ) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. Direct infusion of IL-15 or BDNF in the brain of mice transplanted with glioma significantly reduces tumour growth. We demonstrate that brain infusion of IL-15 increases the frequency of NK cell infiltrating the tumour and that NK cell depletion reduces the efficacy of EE and IL-15 on tumour size and of EE on mice survival. BDNF infusion reduces M/Mφ infiltration and CD68 immunoreactivity in tumour mass and reduces glioma migration inhibiting the small G protein RhoA through the truncated TrkB.T1 receptor. These results suggest alternative approaches for glioma treatment.

IntroductionNatural killer (NK) cells are a lymphocyte subset that contributes to the early host response to viral infection and cancer by promoting contact-dependent cytotoxicity and producing cytokines upon recognition of altered cells. [1][2][3] These functions are acquired mainly during differentiation in the bone marrow (BM) that provides cytokine-and growth factor-mediated signals along with the adhesive support required for NK cell development. 4,5 Sequential steps of mouse NK cell differentiation and maturation have been recently characterized 6,7 : NK cells derive from a lymphoid precursor (pNK) expressing the common IL2R/IL15R beta chain (CD122) and the activating receptor NKG2D and lacking lineage markers. Immature NK (iNK) cells express NK1.1 and CD94 along with the alpha v integrin chain (CD51) and low levels of CD11b expression, and have poor cytotoxic and cytokine secretion capacity. During maturation, an intimate contact with IL15-presenting cells drives Ly49 C-type lectin receptor expression and a phase of proliferationdependent expansion. 8,9 Mature NK (mNK) cells acquire CD49b (defined by the DX5 mAb clone) and lose CD51 expression; among this population, cells with increased expression of CD11b and CD43 are considered fully functional. The phenotypic and functional heterogeneity of NK cells in the peripheral organs, together with the observation that also pNK and iNK can be found outside BM, suggest that the BM is involved mainly in the initial steps of NK cell differentiation, and that final maturation also occurs in different organs. 6,[10][11][12] Leukocyte development in the BM is characterized by changes in their migration properties that enable coordinated relocation of individual precursors during their sequential stages of maturation.Chemokines are a family of small polypeptides that, together with adhesion receptors, control leukocyte trafficking in homeostatic and inflammatory conditions by regulating migration from the blood into tissues and subsequent microenvironmental localization within the tissues. [13][14][15] Changes in the migration properties during leukocyte development are reflected by switches in chemokine receptor profile and expression of selected chemokines in distinct microenvironments. 16,17 In addition, chemokines such as CXCL8 and CCL3 that are secreted by BM stromal cells in response to basal or inflammatory stimuli are potent mobilizing factors for selected BM cell populations. 18-21 Thus, chemokines can regulate both retention/ mobilization of leukocytes from the BM to the blood and their recruitment into tissues.NK cell subsets localize in several organs such as spleen, liver, lung, uterus, along with BM during steady state, [10][11][12]22 and it is likely that NK cell trafficking in these organs is controlled by chemotactic receptors. Consistently, Walzer et al recently demonstrated that the lysophospholipid S1P receptor S1P 5 provides an egress signal for both BM and lymph node NK cells. 23 Upon stimulation, NK cells are recruited in a chemokinedependent ma...

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Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice.