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.

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.

During development in the bone marrow (BM), NK-cell positioning within specific niches can be influenced by expression of chemokine or adhesion receptors. We previously demonstrated that the maintenance in the BM of selected NK-cell subsets is regulated by the CXCR4/CXCL12 axis. In the present study, we showed that CX3CR1 is prevalently expressed on KLRG1 ؉ NK cells, a subset considered terminally differentiated. Two KLRG1 ؉ NKcell populations endowed with distinct homing and functional features were defined according to CX3CR1 expression. In the BM, KLRG1 ؉ /CX3CR1 ؊ NK cells were mainly positioned into parenchyma, while KLRG1 ؉ /CX3CR1 ؉ NK cells exhibited reduced CXCR4 expression and were preferentially localized in the sinusoids. We also showed that ␣ 4 integrin plays a pivotal role in the maintenance of NK cells in the BM sinusoids and that ␣ 4 neutralization leads to strong reduction of BM KLRG1 ؉ /CX3CR1 ؉ NK cells. Moreover, we found that KLRG1 ؉ /CX3CR1 ؉ cells originate from KLRG1 ؉ /CX3CR1 ؊ NK-cell population and display impaired capability to produce IFN-␥ and to lyse YAC-1 target cells on cytokine stimulation. Altogether, our findings show that CX3CR1 represents a marker of a KLRG1 ؉ NK-cell population with unique properties that can irreversibly differentiate from the KLRG1 ؉ /CX3CR1 ؊ NK cells during steady state conditions. (Blood. 2011;117(17): 4467-4475) IntroductionNatural killer (NK) cells represent a lymphocyte population of the innate immunity distributed in several lymphoid and nonlymphoid organs and involved in host defense against microbial infections and cell transformation. [1][2][3][4] Bone marrow (BM) is the main site of NK-cell generation, providing both cellular substrates and signals required to sustain cell proliferation and differentiation. 5,6 During maturation, mouse NK cells gradually modulate the expression of several surface receptors including cytokine receptors (ie, CD122 or CD127), adhesion molecules (ie, integrins) and receptors with activating or inhibitory functions (ie, CD94, NKG2 and Ly49 receptors). 7 The acquisition of CD49b expression (␣ 2 integrin chain, recognized by DX5 monoclonal antibody) is an early event occurring during development and defines a heterogeneous population of mature NK cells. 8 According to the expression of the integrin chain CD11b (also known as Mac-1 or ␣ m ) 2 major NK-cell subsets have been defined: a less differentiated population expressing low receptor levels (CD11b low ) and a more differentiated one expressing higher levels (CD11b high ) of the integrin. 9 In addition, down-modulation of the tumor necrosis factor receptor superfamily member, CD27, by the CD11b high subset coincides with the acquisition of the killer lectin-like receptor G1 (KLRG1) expression, an inhibitory receptor that binds to several members of the cadherin family. [10][11][12][13] KLRG1 is generally considered a marker of terminally differentiated NK and T cells [14][15][16][17] that can also be acquired after homeostatic proliferation, and defines a subset of...