Regulation Of Antiviral Immune Responses Research Articles

The Laboratory of Genetics and Physiology 2: Emerging Insights into the Controversial Functions of This RIG-I-Like Receptor

The laboratory of genetics and physiology 2 (LGP2) is a key component of the RNA helicase family of retinoic acid-inducible gene 1- (RIG-I-) like receptors (RLRs) and is widely involved in viral RNA recognition and regulation during innate immune responses. Unlike RIG-I and melanoma differentiation-associated 5, both RLR members, LGP2 lacks the caspase-recruitment domain (CARD), which is required for recruiting and interacting with downstream signaling proteins to activate a cascade of downstream signaling events. The absence of the CARD results in divergent functional performance for LGP2 compared to these other RLR members. Both negative and positive regulatory roles have been reported for LGP2 in antiviral immune responses. It is currently unclear how the unusual properties of LGP2 mediate opposing roles. Future studies should elucidate the molecular mechanism(s) of LGP2 action. This minireview provides a brief overview of LGP2 structure and functions, with an expanded discussion on the regulation mechanisms in response to viral infection, hopefully stimulating insight into the divergent roles of LGP2 in the regulation of antiviral immune responses.

Regulation of Antiviral CD8 T-Cell Responses

A balanced immune response to a viral pathogen leads to clearance of the virus while limiting immune mediated pathology. Control of this process occurs at all stages of the immune response, including during the induction of an antiviral response, clearance of virally infected cells, and the resolution of this response. Regulation of antiviral immune response is further modified when the immune system fails to clear the pathogen and by the nature of chronic infection itself. A number of processes have been implicated in the regulation of antiviral immune responses, such as the limitation of viral antigen load by interferons, apoptosis through cytokine withdrawal or Fas-mediated killing, and control of these responses by regulatory T cells. This review addresses several of these mechanisms.

DNA inhibits dsRNA-induced secretion of pro-inflammatory cytokines by gingival fibroblasts

Nucleic acids interacting with pattern-recognizing receptors (PRRs), such as Toll-like-(TLRs), RIG-I-like receptors (RLRs) and dsDNA-receptors activate innate immune response in non-professional immune cells and thus the production of pro-inflammatory cytokines. Along with bacterial and viral nucleic acids, endogenous cell-free and cell-surface-bound extracellular DNA (exDNA and csbDNA) could interact with PRRs and possess immunomodulating activity.To elucidate if exDNA influence innate immunity a comparative study of exDNA, genomic and plasmid DNA on interleukin production in gingival fibroblasts (GF) has been done. All DNA tested have no effect on IL secretion in a broad concentration range (10ng/ml–1μg/ml). Simultaneous treatment of cells with DNA and dsRNA analog poly(I:C) leads to inhibition of poly(I:C)-activated secretion of IL-6 and IL-8. Cell-surface-bound DNA possesses two times stronger inhibiting effect as compared to genomic DNA indicating the enrichment of csbDNA in sequences providing such activity. Effects of several recently found specific DNA sequences tightly bound with cell surface have been tested. Joint stimulation of GF with poly(I:C) and deoxyribooligonucleotides (ODN), containing such sequences, demonstrates that both ssODN and dsODN possess sequence-dependent inhibiting effect. Inhibition of IL production after colipofection of ODN and poly(I:C) into cells indicates the involvement of RLRs or other cytoplasmic factors in the effect. The data obtained indicate that endogenous DNA might be involved in regulation of antiviral immune response and sequence-specific ODNs are potential inhibitors of the inflammation induced by viral infection.

Immunosuppressive mechanisms during viral infectious diseases.

For a virus to establish persistence in the host, it has to exploit the host immune system such that the active T-cell responses against the virus are curbed. On the other hand, the goal of the immune system is to clear the virus, following which the immune responses need to be downregulated, by a process known as immunoregulation. There are multiple known immunoregulatory mechanisms that appear to play a role in persistent viral infections. In the recent past, IL-10 and PD-1 have been identified to be playing a significant role in the regulation of antiviral immune responses. The evidence that viruses can escape immunologic attack by taking advantage of the host’s immune system is found in LCMV infection of mice and in humans persistently infected with HIV and HCV. The recent observation that the functionally inactive T-cells during chronic viral infections can be made to regain their cytokine secretion and cytolytic abilities is very encouraging. Thus, it would be likely that neutralization negative immune regulation during persistent viral infection would result in the preservation of effector T-cell responses against the virus, thereby resulting in the elimination of the persistent infection.

Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS

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.

A statistical analysis of memory CD8 T cell differentiation: An application of a hierarchical state space model to a short time course microarray experiment

CD8 T cells are specialized immune cells that play an important role in the regulation of antiviral immune response and the generation of protective immunity. In this paper we investigate the differentiation of memory CD8 T cells in the immune response using a short time course microarray experiment. Structurally, this experiment is similar to many in that it involves measurements taken on independent samples, in one biological group, at a small number of irregularly spaced time points, and exhibiting patterns of temporal nonstationarity. To analyze this CD8 T-cell experiment, we develop a hierarchical state space model so that we can: (1) detect temporally differentially expressed genes, (2) identify the direction of successive changes over time, and (3) assess the magnitude of successive changes over time. We incorporate hidden Markov models into our model to utilize the information embedded in the time series and set up the proposed hierarchical state space model in an empirical Bayes framework to utilize the population information from the large-scale data. Analysis of the CD8 T-cell experiment using the proposed model results in biologically meaningful findings. Temporal patterns involved in the differentiation of memory CD8 T cells are summarized separately and performance of the proposed model is illustrated in a simulation study.

Infections, Immunity & their Effects on Asthma

Infections, Immunity & their Effects on Asthma

Enhanced ability of peripheral invariant natural killer T cells to produce IL-13 in chronic hepatitis C virus infection

Human invariant natural killer T (iNKT) cells express a TCR Valpha24-JalphaQ paired with Vbeta11 and are activated by a surrogate ligand, alpha-galactosylceramide (alphaGalCer). The iNKT cells are involved in the regulation of anti-viral immune responses; however, little is known about their roles in hepatitis C virus (HCV) infection. We compared the frequency of peripheral iNKT cells and their cytokine producing capacity reactive to alphaGalCer between chronically HCV-infected patients and healthy subjects. Cytokine production of freshly isolated iNKT cells were analyzed by ELISPOT. Activated iNKT cells were obtained by culture with alphaGalCer-loaded dendritic cells (DCs) and re-stimulated with them for the measurement of cytokine production. The frequencies of iNKT cells were not different between HCV-infected patients and healthy subjects. The number of fresh IFN-gamma-producing iNKT cells reactive to alphaGalCer was not different between the patients and controls, whereas fresh iNKT cells produced negligible amounts of Th2 cytokines regardless of HCV infection. In response to alphaGalCer, expanded iNKT cells from the patients secreted IFN-gamma comparable in amount to controls, whereas they released significantly more IL-13 than cells from controls. Activated iNKT cells from HCV-infected patients gain more ability to secrete IL-13 than those from healthy subjects.