IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4+ T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4+ T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4+ T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4+ T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21–producing HIV-specific, but not human CMV-specific, Ag-experienced CD4+ T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4+ T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.

The differentiation of monocytes into macrophages and dendritic cells is accompanied by induction of cell-surface neuraminidase 1 (Neu1) and cathepsin A (CathA), the latter forming a complex with and activating Neu1. To clarify the biological importance of this phenomenon we have developed the gene-targeted mouse models of a CathA deficiency (CathA S190A ) and a double CathA/Neu1 deficiency (CathA S190A-Neo ). Macrophages of CathA S190A-Neo mice and their immature dendritic cells showed a significantly reduced capacity to engulf Grampositive and Gram-negative bacteria and positively and negatively charged polymer beads as well as IgG-opsonized beads and erythrocytes. Properties of the cells derived from CathA S190A mice were indistinguishable from those of wild-type controls, suggesting that the absence of Neu1, which results in the increased sialylation of the cell surface proteins, probably affects multiple receptors for phagocytosis. Previous data showed that mammalian neuraminidase 1 (Neu1), 5 in addition to its role in the intralysosomal catabolism, may be also involved in cellular signaling during the immune response. In particular, during the activation of mouse T cells, Neu1 is expressed on the plasma membrane and is required for the early production of interleukin-4 and for the interaction of T cells with the antigen-presenting cells (8 -12). In addition, Neu1 of T cells converts the group-specific component (Gc protein) into a factor necessary for the inflammation-primed activation of macrophages (13,14). T cells derived from SM/J or B10.SM strains of mice with the reduced Neu1 activity, due to a missense mutation in the Neu1 gene (15), fail to convert Gc and synthesize interleukin-4, whereas B cells of these mice cannot produce IgG 1 and IgE after immunization with pertussis toxin (8,14,16). Strikingly, surface desialylation of macrophages by viral sialidase from Arthrobacter ureafaciens significantly increases their capacity for phagocytosis of influenza virus-infected HeLa cells (17), providing the direct link between the surface sialylation of antigen-presenting cells and their biological activity.Previously we showed that Neu1 increased 14-fold during the differentiation of human monocytes into macrophages (18). * This work was supported in part by Canadian Institutes of Health ResearchOperating Grants MOP 15079 and GOP 38107 and by an equipment grant from Canadian Foundation for Innovation (to A. V. P.

The host invariably responds to infecting viruses by activating its innate immune system and mounting virus-specific humoral and cellular immune responses. These responses are aimed at controlling viral replication and eliminating the infecting virus from the host. However, viruses have evolved numerous strategies to counter and evade host's antiviral responses. Providing specific examples from the published literature, we discuss in this review article various strategies that viruses have developed to evade antiviral cellular responses of the host. Unraveling these viral strategies allows a better understanding of the host-pathogen interactions and their coevolution. This knowledge is important for identifying novel molecular targets for developing antiviral reagents. Finally, it may also help devise new knowledge-based strategies for developing antiviral vaccines.

NK cells play an important role in controlling viral infections. They can kill virus-infected cells directly as well as indirectly via antibody-dependent, cell-mediated cytotoxicity. They need no prior sensitization and expansion for this killing. NK cells are also considered as important regulators of antiviral immune responses. They do so by secreting a multitude of soluble mediators and by directly interacting with other immune cells, e.g., dendritic cells. NK cells do not possess a single well-defined receptor to recognize antigens on target cells. Instead, they express an array of inhibitory and activating receptors and coreceptors, which bind to their cognate ligands expressed on the surface of target cells. These ligands include classical and nonclassical MHC class I antigens, MHC-like proteins, and a variety of other self- and virus-derived molecules. They may be expressed constitutively and/or de novo on the surface of virus-infected cells. NK cell receptors (NKRs) of the killer-cell Ig-like receptor (KIR) family, like their MHC class I ligands, are highly polymorphic. Several recent studies suggest that epistatic interactions between certain KIR and MHC class I genes may determine innate resistance of the host to viral infections, including HIV. In the first part of this review article, we provide an overview of the current state of knowledge of NK cell immunobiology and describe how NKR genes, alone and in combination with HLA genes, may determine genetic resistance/susceptibilty to HIV infection and the development of AIDS in humans.

The renin-angiotensin system plays a key role in the initiation and maintenance of elevated blood pressure associated with altered intrauterine milieu. The current studies were undertaken to verify whether vascular response to ANG II is increased in adult offspring of low-protein fed dams (LP) compared with control (CTRL) and if so, to examine underlying mechanism(s). ANG II-induced contraction of carotid rings was increased in LP (E(max), the maximum asymptote of the curve, relative to maximal response to KCl 80 mM: 230 +/- 3% LP vs. 201 +/- 2% CTRL, P < 0.05). In both groups, contraction to ANG II was mediated solely by AT1R. Responses to thromboxane A2 analog U-46619 and to KCl 80 mM under step increases in tension were similar between groups. Endothelium depletion enhanced contraction to ANG II in both groups, more so in LP. Blockade of endothelin formation had no effect on response to ANG II, and ANG-(1-7) did not elicit vasomotor response in either group. Superoxide dismutase (SOD) analog Tempol normalized LP without modifying CTRL response to ANG II. Basal levels of superoxide (aortic segments, lucigenin-enhanced chemiluminescence and fluorescent dye hydroethidine) were higher in LP. ANG II further increased superoxide production in LP only, and this was inhibited by coincubation with diphenylene iodonium or apocynin (inhibitor of NADPH oxidase complex). AT1R expression in carotid arteries was increased in LP, whereas SOD expression was unchanged. In conclusion, vasoconstriction to ANG II is exaggerated in this model of developmental programming of hypertension, secondary to enhanced vascular production of superoxide anion by NADPH oxidase with concomitant increase of AT1R expression.

Acute lymphoblastic leukemia of pre-B cells (pre-B ALL) is the most frequent form of leukemia affecting children in Western countries. Evidence is accumulating that genetic factors play an important role in conferring susceptibility/ resistance to leukemia in children. In this regard, activating killer-cell immunoglobulin-like receptor (KIR) genes are of particular interest. Humans may inherit different numbers of the 6 distinct activating KIR genes. Little is known about the impact of this genetic variation on the innate susceptibility or resistance of humans to the development of B-ALL. We addressed this issue by performing a case-control study in Canadian children of white origin. Our results show that harboring activating KIR genes is associated with reduced risk for developing B-ALL in these children. Of the 6 activating KIR genes, KIR2DS2 was maximally associated with decreased risk for the disease (P ‫؍‬ 1.14 ؋ 10 ؊7 ). Furthermore, our results showed that inheritance of a higher number of activating KIR genes was associated with significant reductions in risk for ALL in children. These results were also consistent across different ALL phenotypes, which included children with pre-T cell ALL. Our study provides novel insights concerning the pathogenesis of childhood leukemia in white children and has implications for the development of new immunotherapies for this cancer. (Blood. 2011;118(5): 1323-1328)

As is the case in other viral infections, humans respond to HIV infection by activating their NK cells. However, the virus uses several strategies to neutralize and evade the host's NK cell responses. Consequently, it is not surprising that NK cell functions become compromised in HIV-infected individuals in early stages of the infection. The compromised NK cell functions also adversely affect several aspects of the host's antiviral adaptive immune responses. Researchers have made significant progress in understanding how HIV counters NK cell responses of the host. This knowledge has opened new avenues for immunotherapy and vaccination against this infection. In the first part of this review article, we gave an overview of our current knowledge of NK cell biology and discussed how the genes encoding NK cell receptors and their ligands determine innate genetic resistance/susceptibilty of humans against HIV infections and AIDS. In this second part, we discuss NK cell responses, viral strategies to counter these responses, and finally, their implications for anti-HIV immunotherapy and vaccination.

IL-37 is a cytokine belonging to the IL-1 family. Although discovered in silico in 2000, significant advances in the understanding of its biology were made only in recent years. It is a member of the family with potent anti-inflammatory and immunosuppressive properties. It is produced as a precursor without a classic signal peptide. The precursor is cleaved into mature form in the cytoplasm by caspase-1. A small fraction of the cleaved IL-37 binds SMAD-3, translocates to the nucleus, and suppresses transcription of several proinflammatory genes. Both precursor and cleaved forms of IL-37 are secreted. They bind IL-18Rα chain (also used by IL-18 as a receptor subunit) and recruit Toll/IL-1R (TIR)-8 for transducing intracellular signaling. TIR-8 is a member of the IL-1 receptor family (IL-1RF) and was previously known as an orphan receptor. IL-37 suppresses activation of NF-κB and MAPK and activates Mer-PTEN-DOK pathway. It negatively regulates signaling mediated by TLR agonists, proinflammatory cytokines, and IL-1RF ligands. It also affects cell metabolism by inhibiting mTOR, GSK-3α/β, and activating AMPK. Despite having the ability to dampen host's immune responses, the cytokine has been shown to exert antitumor effects, and it has been suggested that it may act as a prognostic marker in a variety of human cancers. Recent studies have suggested that IL-37 may represent a novel therapeutic tool in patients with cancer. In this review, we provide an overview of the cytokine biology, discuss recent advances made in unraveling its anti-cancer effects, and suggest guidelines for future research.