Christopher E. Andoniou

Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity

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-α and interactions between the NKG2D activating receptor and NKG2D ligand, whereas the production of interferon-γ 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-α 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.

Infection of dendritic cells by murine cytomegalovirus induces functional paralysis

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.

Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene

v‐cbl is the transforming gene of a murine retrovirus which induces pre‐B cell lymphomas and myelogenous leukaemias. It encodes 40 kDa of a gag fusion protein which is localized in the cytoplasm and nucleus of infected cells. The c‐cbl oncogene encodes a 120 kDa cytoplasmic protein and its overexpression is not associated with tumorigenesis. The c‐cbl sequence has shown that v‐cbl was generated by a truncation that removed 60% of the C‐terminus. In this study, we carried out experiments to identify the position within cbl where the transition occurs between non‐tumorigenic and tumorigenic forms. These experiments focused attention on a region of 17 amino acids which is deleted from cbl in the 70Z/3 pre‐B lymphoma due to a splice acceptor site mutation. This mutation activates cbls tumorigenic potential and induces its tyrosine phosphorylation. We also show that the expression of the v‐abl and bcr‐abl oncogenes results in the induction of cbl tyrosine phosphorylation, and that abl and cbl associate in vivo. These findings demonstrate that tyrosine‐phosphorylated cbl promotes tumorigenesis and that cbl is a downstream target of the bcr‐abl and v‐abl kinases.

A Contribution of Mouse Dendritic Cell–Derived IL-2 for NK Cell Activation

Dendritic cells (DCs) play a predominant role in activation of natural killer (NK) cells that exert their functions against pathogen-infected and tumor cells. Here, we used a murine model to investigate the molecular mechanisms responsible for this process. Two soluble molecules produced by bacterially activated myeloid DCs are required for optimal priming of NK cells. Type I interferons (IFNs) promote the cytotoxic functions of NK cells. IL-2 is necessary both in vitro and in vivo for the efficient production of IFNγ, which has an important antimetastatic and antibacterial function. These findings provide new information about the mechanisms that mediate DC–NK cell interactions and define a novel and fundamental role for IL-2 in innate immunity.

Innate immunity defines the capacity of antiviral T cells to limit persistent infection

Effective immunity requires the coordinated activation of innate and adaptive immune responses. Natural killer (NK) cells are central innate immune effectors, but can also affect the generation of acquired immune responses to viruses and malignancies. How NK cells influence the efficacy of adaptive immunity, however, is poorly understood. Here, we show that NK cells negatively regulate the duration and effectiveness of virus-specific CD4+ and CD8+ T cell responses by limiting exposure of T cells to infected antigen-presenting cells. This impacts the quality of T cell responses and the ability to limit viral persistence. Our studies provide unexpected insights into novel interplays between innate and adaptive immune effectors, and define the critical requirements for efficient control of viral persistence.

CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10–driven MARCH1-mediated ubiquitination and degradation

By opposing IL-10–driven, MARCH1-mediated ubiquitination and degradation of MHC class II, CD83 may boost the immunogenicity of dendritic cells.

Natural killer cells in viral infection: more than just killers

Summary:  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.

Killers and beyond: NK-cell-mediated control of immune responses

Effective immunity requires coordinated activation of innate and adaptive immune responses. NK cells are principal mediators of innate immunity, able to respond to challenge quickly and generally without prior activation. The most acknowledged functions of NK cells are their cytotoxic potential and their ability to release large amounts of cytokines, especially IFN‐γ. Recently, it has become clear that NK cells are more than assassins. Indeed, NK cells play critical roles in shaping adaptive immunity.

TRAIL+ NK Cells Control CD4+ T Cell Responses during Chronic Viral Infection to Limit Autoimmunity

Natural killer (NK) cells have been reported to control adaptive immune responses that occur in lymphoid organs at the early stages of immune challenge. The physiological purpose of such regulatory activity remains unclear, because it generally does not confer a survival advantage. We found that NK cells specifically eliminated activated CD4(+) T cells in the salivary gland during chronic murine cytomegalovirus (MCMV) infection. This was dependent on TNF-related apoptosis inducing ligand (TRAIL) expression by NK cells. Although NK cell-mediated deletion of CD4(+) T cells prolonged the chronicity of infection, it also constrained viral-induced autoimmunity. In the absence of this activity, chronic infection was associated with a Sjogrens-like syndrome characterized by focal lymphocytic infiltration into the glands, production of autoantibodies, and reduced saliva and tear secretion. Thus, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity.

Loss of c-Cbl RING finger function results in high-intensity TCR signaling and thymic deletion.

Signaling from the T‐cell receptor (TCR) in thymocytes is negatively regulated by the RING finger‐type ubiquitin ligase c‐Cbl. To further investigate this regulation, we generated mice with a loss‐of‐function mutation in the c‐Cbl RING finger domain. These mice exhibit complete thymic deletion by young adulthood, which is not caused by a developmental block, lack of progenitors or peripheral T‐cell activation. Rather, this phenotype correlates with greatly increased expression of the CD5 and CD69 activation markers and increased sensitivity to anti‐CD3‐induced cell death. Thymic loss contrasts the normal fate of the c‐Cbl–/– thymus, even though thymocytes from both mutant mice show equivalent enhancement in proximal TCR signaling, Erk activation and calcium mobilization. Remarkably, only the RING finger mutant thymocytes show prominent TCR‐directed activation of Akt. We show that the mutant c‐Cbl protein itself is essential for activating this pathway by recruiting the p85 regulatory subunit of PI 3‐kinase. This study provides a unique model for analyzing high‐intensity TCR signals that cause thymocyte deletion and highlights multiple roles of c‐Cbl in regulating this process.