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Heparanase is a β-d-endoglucuronidase that cleaves heparan sulphate, a key component of the ECM and basement membrane. The remodelling of the ECM by heparanase has been proposed to regulate both normal physiological and pathological processes, including wound healing, inflammation, tumour angiogenesis and cell migration. Heparanase is also known to exhibit non-enzymatic functions by regulating cell adhesion, cell signalling and differentiation. In this study, constitutive heparanase-deficient (Hpse(-/-) ) mice were generated on a C57BL/6 background using the Cre/loxP recombination system, with a complete lack of heparanase mRNA, protein and activity. Although heparanase has been implicated in embryogenesis and development, Hpse(-/-) mice are anatomically normal and fertile. Interestingly, consistent with the suggested function of heparanase in cell migration, the trafficking of dendritic cells from the skin to the draining lymph nodes was markedly reduced in Hpse(-/-) mice. Furthermore, the ability of Hpse(-/-) mice to generate an allergic inflammatory response in the airways, a process that requires dendritic cell migration, was also impaired. These findings establish an important role for heparanase in immunity and identify the enzyme as a potential target for regulation of an immune response., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

NK cells have been proposed to be an initial source of IFN-gamma that supports either Th1 or CTL priming. Although NK cells reside in naive lymph nodes (LN) at a very low frequency, they can be recruited into LN draining sites of infection, inflammation, or immunization where they potentially influence adaptive immunity. In this study, we report that mature CD27(high) NK cells are predominantly recruited into the draining LN following dendritic cell (DC) challenge. Importantly, the recruitment of the CD27(high) NK cell subset in the draining LN was dependent on host IFN-gamma and the activation status of NK cells. Endogenous epidermal DC migration induced by hapten challenge also triggers NK cell recruitment to the draining LN in an IFN-gamma-dependent mechanism. Thus, our results identify that CD27(high) NK cells are the dominant population recruited to the draining LN and NK cell recruitment requires endogenous IFN-gamma in coordinating with DC migration.

If one envisions dendritic cells (DCs) as nature's adjuvant, then it is easy to predict that they would be advantageous for cancer immunotherapy. Advances in culture processes that generate large numbers of purified and functionally mature DCs raised the possibility that DCs might be promising clinical agents to generate effective immune responses against cancer. The use of mature DCs as cellular vaccines was proposed to be superior to conventional strategies aimed at treating cancer, yet a phase III clinical trial in patients with melanoma demonstrated no increased benefit of DCs over standard therapy. Despite this and other apparent failures, we propose that DC-based therapy should not be discarded but rather reassessed. The heterogeneity of DCs and their interaction with other innate cells and regulatory and effector pathways must be clearly understood before the full therapeutic benefit of DCs are recognized. Several aspects of DC vaccination require optimization including the following: effective delivery of vaccines to DCs in lymphoid tissues; incorporation of components that induce appropriate DC activation; and facilitation of innate and adaptive interactions and reduction of regulatory T-cell networks or suppressive microenvironments that hinder the function of immune effectors. Application of this knowledge is resulting in encouraging new data in pre-clinical settings, where multiple arms of the immune system are targeted for cancer therapy.

Innate immunity was believed originally to serve simply as the first-line defense against infection and malignancy, with adaptive immunity imposing specificity and ensuring that appropriate responses are mounted against chronic or reoccurring challenges. In this model of immunity, innate and adaptive immune responses are sequential, essentially non-overlapping, and interactions between components of each response limited or non-existent. Over the last 5 years, it has become increasingly evident that interactions between elements of the innate and adaptive immune systems are common. Indeed, it is now clear that the generation and maintenance of effective immunity require an extensive array of interactions between multiple components of the immune system. This review discusses recent advances in this area with particular emphasis on the role of natural killer cells in shaping the adaptive immune response to viral infection.

Dendritic cells (DCs) regulate various aspects of innate immunity, including natural killer (NK) cell function. Here we define the mechanisms involved in DC-NK cell interactions during viral infection. NK cells were efficiently activated by murine cytomegalovirus (MCMV)-infected CD11b(+) DCs. NK cell cytotoxicity required interferon-alpha and interactions between the NKG2D activating receptor and NKG2D ligand, whereas the production of interferon-gamma by NK cells relied mainly on DC-derived interleukin 18. Although Toll-like receptor 9 contributes to antiviral immunity, we found that signaling pathways independent of Toll-like receptor 9 were important in generating immune responses to MCMV, including the production of interferon-alpha and the induction of NK cell cytotoxicity. Notably, adoptive transfer of MCMV-activated CD11b(+) DCs resulted in improved control of MCMV infection, indicating that these cells participate in controlling viral replication in vivo.

Dendritic cells (DC), first characterized in 1973 by Steinman and Cohn, have been defined as the professional antigen presenting cells (APC), capable of activating naïve T cells much more efficiently than either B cells or macrophages. DC also capture and process antigen more efficiently than other APC, and offer MHC-antigen complexes to T cells at higher densities, and in the context of larger amounts of co-stimulatory molecules (i.e. CD40, CD80 and CD86) at the T cell-DC synapse. Although historically, the principal function of DC is the priming of naïve T cells, more recently they have also been shown to affect the functions of natural killer (NK) cells. Interactions between DC and NK cells may be critical in situations where immune surveillance requires efficient early activation of NK cells, as is the case during infections. This review aims to summarise the interactions that occur between DC and NK cells during viral infection.

Infection with murine cytomegalovirus (MCMV) has contributed to understanding many aspects of human infection and, additionally, has provided important insight to understanding complex cellular responses. Dendritic cells (DCs) are a major target for MCMV infection. Here, we analyze the effects of MCMV infection on DC viability, and show that infected DCs become resistant to apoptosis induced by growth factor deprivation. The precise contribution of changes in the expression of Bcl-2 family proteins has been assessed and a new checkpoint in the apoptotic pathway identified. Despite their resistance to apoptosis, MCMV-infected DCs showed Bax to be tightly associated with mitochondria and, together with Bak, forming high molecular weight oligomers, changes normally associated with apoptotic cell death. Exposure of a constitutively occluded Bax NH2-terminal epitope was blocked after infection. These results suggest that MCMV has evolved a novel strategy for inhibiting apoptosis and provide evidence that apoptosis can be regulated after translocation, integration, and oligomerization of Bax at the mitochondrial membrane.

Ly49H(+)NK1.1(+) natural killer (NK) cells are essential for the control of murine cytomegalovirus (MCMV) during the acute stage of infection. This cell subset expands at the later stages of infection in an MCMV-specific fashion. Here we demonstrate a critical interaction between Ly49H(+) NK cells and CD8alpha(+) dendritic cells (DCs) whereby the presence of Ly49H(+) NK cells results in maintenance of CD8alpha(+) DCs in the spleen during acute MCMV infection. Reciprocally, CD8alpha(+) DCs are essential for the expansion of Ly49H(+) NK cells by a mechanism involving interleukin 18 (IL-18) and IL-12. This study provides evidence for a functional interrelationship between DCs and NK cells during viral infection and defines some of the critical cytokines.

Cytomegalovirus (CMV), measles and HIV are the main human pathogens known to induce immunosuppression. Unlike measles and HIV, and despite the availability of a well studied animal model, little is known about the mechanisms that control CMV-induced immunosuppression. We hypothesized that dendritic cells (DCs), which are crucial in generating and maintaining immune responses, represent a target for CMV and that the transient, but profound, immunosuppression that accompanies CMV infection results from viral interference with DC functions. Here we show that DCs were permissive to murine CMV infection. In addition, DC infection prevented delivery of the signals required for T cell activation. Thus, CMV-mediated impairment of DC function may be crucial for virally induced immunosuppression and interleukin 2 is implicated as a key factor.