IntroductionCirculating monocytes are precursors that can differentiate into a variety of tissue-resident macrophages (M⌽s) or dendritic cells (DCs), and even osteoclasts. 1 M⌽s exhibit a variety of activities, some of which are in opposition (ie, proinflammatory versus anti-inflammatory, immunostimulatory versus immunosuppressive, and tissue destructive versus reconstructive). 1 The functional heterogeneity of M⌽s depends, at least in part, on the local microenvironment. 2,3 In analogy with the Th1/Th2 dichotomy of T-cell responses, M⌽s exposed to IFN␥ or IL-4 have been referred to as M1s or M2s (also called alternatively activated M⌽s), respectively. 4 M1s produce IL-12 and TNF␣ and are potent killers of microorganisms (especially intracellular pathogens) and tumor cells. M2s produce IL-10 but not IL-12, scavenge debris, tune inflammatory responses, and promote humoral immunity and tissue repair. 5 The detection in cancer patients of tumor-specific T cells that kill ex vivo autologous tumor cells demonstrates that numerous tumor-cell types are potentially immunogenic. However, spontaneous clearance of established tumors by immune mechanisms is rare and active antitumor immunotherapy usually has poor clinical efficacy. 6 It is now largely documented that established tumors propagate conditions that favor their immune escape. 6 Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) accumulate at tumor sites and maintain immune tolerance that contributes to defeating tumor immunity. 6,7 TAMs are far more abundant than Tregs and, in various solid tumors, constitute the major components of the leukocyte infiltrate. In most cases, especially breast, prostate, cervical, and ovarian cancers, TAM density is correlated with poor prognosis. [8][9][10] Strong evidence suggests that TAMs also promote cancer progression and metastasis. 8,11,12 TAMs are polarized M2 cells with potent immunosuppressive functions. They have poor antigen-presenting capacity, prevent T-cell activation, and may contribute to suppressing DC functions. 4,13,14 They also promote the recruitment of Tregs and Th2 cells (through CC chemokine ligand 17 [CCL17] and CCL22 secretion) and naive T cells (through CCL18). Naive T-cell activation, in an environment dominated by immature DCs and TAMs, is likely to induce anergy. 10,15 In addition, TAM production of growth and angiogenic factors (ie, vascular endothelial growth factor [VEGF] and platelet-derived endothelial cell growth factor [PDGF]), proteases (ie, matrix metalloproteinase 9 [MMP9]), and chemokines (eg, CCL2) favors tumor-cell proliferation, angiogenesis, dissolution of connective tissues, and metastasis. 8,12,14,16 The origin of TAMs has mostly been studied in mice in terms of precursor recruitment, survival, and proliferation. TAMs derive from circulating monocytes that are recruited into tumors by chemotactic factors, such as monocyte-colony-stimulating factor Submitted February 19, 2007; accepted August 29, 2007. Prepublished online as Blood First Edition paper, September 11, 2...

Food odours are major determinants for food choice; their detection is influenced by nutritional status. Among different metabolic signals, insulin plays a major role in food intake regulation. The aim of the present study was to investigate a potential role of insulin in the olfactory mucosa (OM), using ex vivo tissues and in vitro primary cultures. We first established the expression of insulin receptor (IR) in rat olfactory mucosa. Transcripts of IR-A and IR-B isoforms, as well as IRS-1 and IRS-2, were detected in OM extracts. Using immunocytochemistry, IR protein was located in olfactory receptor neurones, sustentacular and basal cells and in endothelium of the lamina propria vessels. Moreover, the insulin binding capacity of OM was quite high compared to that of olfactory bulb or liver. Besides the main pancreatic insulin source, we demonstrated insulin synthesis at a low level in the OM. Interestingly 48 h of fasting, leading to a decreased plasmatic insulin, increased the number of IR in the OM. Local insulin concentration was also enhanced. These data suggest a control of OM insulin system by nutritional status. Finally, an application of insulin on OM, aiming to mimic postprandial insulin increase, reversibly decreased the amplitude of electro-olfactogramme responses to odorants by approximately 30%. These data provide the first evidence that insulin modulates the most peripheral step of odour detection at the olfactory mucosa level.

NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-c induced by polyI:C plus IL-2/IL-12. Similarly, IFN-c production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 À/À compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-c production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-c and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.Key words: IFN-g . NK cells . PolyI:C . Type I IFN IntroductionType I IFN is a multi-member cytokine family, in which IFN-a and -b are the main types of interest from an immunological perspective [1,2]. They are involved in anti-viral immunity and in some immune disorders (such as autoimmune diseases). In addition to directly interfering with viral replication, type I IFN have anti-proliferative and immunoregulatory properties. They bridge innate and adaptive immune responses by inducing DC maturation and favoring antigen cross-presentation [3]. They also act directly on CD8 1 T cells to favor the generation of effector and memory T cells [4]. The expression of type I IFN is induced early upon recognition of viruses or viral moieties by some innate receptors of the TLR or RIG-1-like receptor families [5]. IFN-a is mainly secreted by plasmacytoid DC in response to viral nucleic acids recognized by TLR7 and 9 [6]. IFN-b mRNA expression is induced in numerous cell types by TLR stimulation [7,8]. IFN-b has a short half-time, is difficult to quantify, and its secretion is mainly evidenced indirectly by neutralizing its activity in in vitro assay [9]. Owing to the central role of type I IFN in the [11]. These cells kill virally infected cells and tumoral cells in the absence of prior activation [11,12]. NK-cell cytotoxic activity is tightly regulated by inhibitory and activatory receptors [13]. Consequently, NK cells are important during the early phases of viral infection, while antigen-specific T-and B-cell responses are generated. In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK c...