The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy.
Abstract T cell-mediated rejection of tumors requires signals from the T cell receptor and co-stimulatory molecules to license effector functions of tumor-antigen specific T cells. There is also an array of immune suppressive mechanisms within the tumor microenvironment that can suppress anti-tumor immunity. The use of monoclonal antibodies to overcome this suppression and/or enhance tumor-antigen specific T cell responses has shown promise in clinical trials. In particular, targeting co-stimulatory members of the tumor necrosis factor receptor (TNFR) family with agonist Abs enhances T cell function, which has led...
Source: Current Opinion in Immunology - February 13, 2013 Category: Allergy & Immunology Authors: Moran AE, Kovacsovics-Bankowski M, Weinberg AD Tags: Curr Opin Immunol Source Type: research

Transcriptional regulation of the NKT cell lineage.
Abstract How expression of canonical semi-invariant TCRs leads to innate-like effector differentiation is a central enigma of NKT cell development. NKT thymic precursors undergo elevated TCR signals leading to increased Egr2, which directly induces their signature transcription factor, PLZF. PLZF is necessary and sufficient to induce a multipotent, unbiased effector program that precedes terminal differentiation into T-bet(high) NK1.1(+) (NKT1) cells and recently identified NKT2 and NKT17 sublineages. Major variations in polarized NKT sublineages have been uncovered in different mouse strains and in several mutant...
Source: Current Opinion in Immunology - February 8, 2013 Category: Allergy & Immunology Authors: Constantinides MG, Bendelac A Tags: Curr Opin Immunol Source Type: research

Natural Killer T cell obsession with self-antigens.
Abstract Natural Killer T (NKT) cells are distinct lymphocyte lineages that recognize lipid antigens presented by the non-classical Major Histocompatibility Complex molecule CD1d. Two categories of NKT cells, type I and type II, have been described based on T-cell receptor expression and antigenic specificity. In both cases, increasing evidence suggest that recognition of self-antigens by these cells plays an important role not only in their development but also in their regulation of a broad range of immune responses. Here we review recent advances in our understanding of how and when NKT cell autoreactivity mani...
Source: Current Opinion in Immunology - February 2, 2013 Category: Allergy & Immunology Authors: Gapin L, Godfrey DI, Rossjohn J Tags: Curr Opin Immunol Source Type: research

Lymphotoxin network pathways shape the tumor microenvironment.
Abstract Accumulating evidence indicates that Lymphotoxin (LT)-β related cytokines directly contribute to the phenotype of cancer cells and alter the tumor microenvironment. Lymphotoxins are part of a cytokine network well known in controlling the development and homeostasis of secondary lymphoid organs. In the adult, the LT network takes on the responsibility of generating inflammatory microenvironments that control innate and adaptive immune responses involved in host defense. This review provides a perspective of the emerging evidence implicating the LT Network in the development and progression of various...
Source: Current Opinion in Immunology - January 19, 2013 Category: Allergy & Immunology Authors: Bjordahl RL, Steidl C, Gascoyne RD, Ware CF Tags: Curr Opin Immunol Source Type: research

Materials based tumor immunotherapy vaccines.
Abstract Immunotherapy is a promising approach for treating cancer. However, there are limitations inherent to current approaches which may be addressed by integrating them with biomaterial-based strategies. Material platforms have been fabricated to interact with immune cells through spatially controlled and temporally controlled delivery of immune modulators and to promote immune cell crosstalk. Particle vaccines have been developed to specifically target and deliver agents to organs, cells and subcellular compartments. These strategies have been shown to generate antigen-specific CTL responses and, in some case...
Source: Current Opinion in Immunology - January 18, 2013 Category: Allergy & Immunology Authors: Li WA, Mooney DJ Tags: Curr Opin Immunol Source Type: research

Sensing of cell death by myeloid C-type lectin receptors.
Abstract Molecules associated with dead or dying cells can be detected by receptors on macrophages and dendritic cells. Signals from these receptors impact myeloid cell function and play a role in determining whether death is silent or proinflammatory, tolerogenic or immunogenic. Prominent among myeloid receptors detecting dead cells are C-type lectin receptors (CLRs). Signals from these receptors variably induce endocytosis of cell corpses, corpse degradation, retrieval of dead cell-associated antigens and/or modulation of immune responses. The sensing of tissue damage by myeloid CLRs complements detection of pat...
Source: Current Opinion in Immunology - January 16, 2013 Category: Allergy & Immunology Authors: Sancho D, Reis E Sousa C Tags: Curr Opin Immunol Source Type: research

DNA recognition in immunity and disease.
Abstract Great progress has been made in understanding how immune cells detect microbial pathogens. An area that has received particular attention is nucleic acid sensing where RNA and DNA sensing machineries have been uncovered. For DNA, TLR9 in endosomes and numerous cytoplasmic DNA binding proteins have been identified. Several of these have been proposed to couple DNA recognition to induction of type I IFNs, pro-inflammatory cytokines and/or caspase-1 activation. Given the ubiquitous expression of many of these DNA binding proteins and the significant potential for endogenous DNA to engage these molecules, it ...
Source: Current Opinion in Immunology - January 9, 2013 Category: Allergy & Immunology Authors: Holm CK, Paludan SR, Fitzgerald KA Tags: Curr Opin Immunol Source Type: research

Regulation of NF-κB by ubiquitination.
Regulation of NF-κB by ubiquitination. Curr Opin Immunol. 2013 Jan 8; Authors: Chen J, Chen ZJ Abstract The nuclear factor κ enhancer binding protein (NF-κB) family of transcription factors regulates the expression of a large array of genes involved in diverse cellular processes including inflammation, immunity and cell survival. Activation of NF-κB requires ubiquitination, a highly conserved and versatile modification that can regulate cell signaling through both proteasome dependent and independent mechanisms. Studies in the past few years have provided new insights into the mecha...
Source: Current Opinion in Immunology - January 8, 2013 Category: Allergy & Immunology Authors: Chen J, Chen ZJ Tags: Curr Opin Immunol Source Type: research

Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments.
Abstract The protein NLRP3 has emerged as a central regulator in the inflammatory process, being implicated directly in hereditary cryopyrinopathies, and indirectly in diseases such as gout, Type 2 diabetes and atherosclerosis. NLRP3 is an important regulator of caspase-1, the enzyme that processes the immature form of IL-1β into the active protein. The control of NLRP3 has therefore become a focus of research with evidence for redox regulation, ubiquitination and regulation by miRNA-223, kinases and calcium all emerging as controllers of NLRP3. As our knowledge expands the prospect for precise pharmacologica...
Source: Current Opinion in Immunology - January 7, 2013 Category: Allergy & Immunology Authors: Haneklaus M, O'Neill LA, Coll RC Tags: Curr Opin Immunol Source Type: research

T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment.
Abstract Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells. Many different molecular and cellular mechanisms contribute to the failure of T cells to eradicate the tumor. These include immune suppressive networks that impair ongoing T cell function and enable tumor escape. Recent studies have started to reveal the nature of effector T cells in the tumor microenvironment. In this article we discuss T cell anergy, exhaustion, senescence, and stemness, and review the phenotype of dysfunctional T cell subsets and the underlying molecular mechanisms in the tumor microenvironme...
Source: Current Opinion in Immunology - January 5, 2013 Category: Allergy & Immunology Authors: Crespo J, Sun H, Welling TH, Tian Z, Zou W Tags: Curr Opin Immunol Source Type: research

TLR3 immunity to infection in mice and humans.
va JL Abstract TLR3 is a receptor for dsRNA, which is generated during most viral infections. However, other cellular processes may also produce dsRNA and there are other receptors for dsRNA. The role of TLR3 in protective immunity to viruses has been investigated in mice and humans with genetically impaired TLR3 responses. TLR3-deficient mice responded to experimental challenge with 16 different viruses in various ways. They were susceptible to eight viruses, normally resistant to three other viruses, and their survival rates were higher than those of wild-type mice following infection with four other viruses. Co...
Source: Current Opinion in Immunology - January 2, 2013 Category: Allergy & Immunology Authors: Zhang SY, Herman M, Ciancanelli MJ, Pérez de Diego R, Sancho-Shimizu V, Abel L, Casanova JL Tags: Curr Opin Immunol Source Type: research

Antigen processing.
PMID: 23287556 [PubMed - as supplied by publisher] (Source: Current Opinion in Immunology)
Source: Current Opinion in Immunology - December 31, 2012 Category: Allergy & Immunology Authors: Sollid LM, Villadangos JA Tags: Curr Opin Immunol Source Type: research

T cell responses to antigen: hasty proposals resolved through long engagements.
Abstract T cells discriminate between peptide-MHC complexes on the surfaces of antigen presenting cells to enact appropriate downstream responses. Great progress has been made over the last 15 years in understanding varied aspects of T cell activation on short timescales (minutes), yet the mechanics and significance of long term T cell receptor signaling (hours or days) remain unclear. Furthermore, there remain some controversies regarding the correlation of the biophysical parameters of ligand-receptor interactions with the scaling of downstream effector functions. Here we review recent studies that emphasize the...
Source: Current Opinion in Immunology - December 28, 2012 Category: Allergy & Immunology Authors: Tkach K, Altan-Bonnet G Tags: Curr Opin Immunol Source Type: research

Tuning the threshold of natural killer cell responses.
Abstract Natural killer cells are lymphocytes of the innate immune system that can kill an array of tumor and infected cells and secrete cytokines that participate in the shaping of the adaptive immune response. While it was believed that NK cell effector responses are acquired during maturation and then fixed, it appears that the threshold of NK cell responsiveness is more adaptable than originally thought. We review here how the local context provides several signals that impact on NK cell differentiation, responsiveness and shapes the antiviral and immunoregulatory outcome of NK cell activation. PMID: 2327...
Source: Current Opinion in Immunology - December 25, 2012 Category: Allergy & Immunology Authors: Narni-Mancinelli E, Ugolini S, Vivier E Tags: Curr Opin Immunol Source Type: research

Policing the cytosol-bacterial-sensing inflammasome receptors and pathways.
Abstract Pattern recognition receptors recognize signals originating from pathogens and comprise a large part of the arsenal in innate immune responses. The NOD-like receptors (NLRs) are one particular class of these receptors that survey the cytoplasm for signs of pathogen invasion. Upon detection, they trigger the formation of a macromolecular complex called the inflammasome that is required for elimination of the pathogen, as well as amplifying a pro-inflammatory response. Although the core machinery has been defined, recent data emphasize the complexity of how NLR inflammasomes function. Here, we highlight new...
Source: Current Opinion in Immunology - December 20, 2012 Category: Allergy & Immunology Authors: Ng TM, Kortmann J, Monack DM Tags: Curr Opin Immunol Source Type: research

Expanding roles for GILT in immunity.
Abstract Gamma-interferon-inducible lysosomal thiol reductase (GILT), a thioredoxin-related oxidoreductase, functions in MHC class II-restricted antigen processing and MHC class I-restricted cross-presentation by reducing disulfide bonds of endocytosed proteins and facilitating their unfolding and optimal degradation. However, recent reports have greatly expanded our understanding of GILT's function. Several studies of GILT and antigen processing have shown that the influence of GILT on the peptide repertoire can alter the character of the immune response and affect central tolerance. Furthermore, a few unexpected...
Source: Current Opinion in Immunology - December 12, 2012 Category: Allergy & Immunology Authors: West LC, Cresswell P Tags: Curr Opin Immunol Source Type: research

Antigen presentation by Langerhans cells.
, Kaplan DH Abstract Langerhans cells and other skin-resident dendritic cells (DC) are required for the development of cutaneous adaptive immune responses. In vivo experiments using mice with selective DC-subset deficiencies and ex vivo experiments using isolated DC suggests that each subset makes a unique contribution to the adaptive response. This review focuses on the functional outcome of antigen presentation by Langerhans cells. Special attention is given to their ability to promote CD4 T cell differentiation in a variety of inflammatory contexts and whether this subset has the capacity to cross-prime CD8 T c...
Source: Current Opinion in Immunology - December 12, 2012 Category: Allergy & Immunology Authors: Igyártó BZ, Kaplan DH Tags: Curr Opin Immunol Source Type: research

The complementary facets of epithelial host defenses in the genetic model organism Drosophila melanogaster: from resistance to resilience.
Abstract Significant advances have been made in our understanding of the host defense against microbial infections taking place at frontier epithelia of Drosophila flies. Immune deficiency (IMD), the major NF-κB immune response pathway induced in these epithelia, displays remarkable adaptations in its activation and regulation in the respiratory and digestive tract. The host defense against ingested pathogens is not limited to resistance, that is, the immune response. It also involves resilience, the capacity of the host to endure and repair damages inflicted by pathogens or the host's own immune response. F...
Source: Current Opinion in Immunology - December 7, 2012 Category: Allergy & Immunology Authors: Ferrandon D Tags: Curr Opin Immunol Source Type: research

Leveraging fluorinated glucosamine action to boost antitumor immunity.
Abstract N-acetyllactosaminyl glycans are key regulators of the vitality and effector function of antitumor T cells. When galectin-1 (Gal-1) binds N-acetyllactosamines on select membrane glycoproteins on antitumor T cells, these cells either undergo apoptosis or become immunoregulatory. Methods designed to antagonize expression or function of these N-acetyllactosamines on N-glycans and O-glycans have thus intensified. Since tumors can produce an abundance of Gal-1, Gal-1 is considered a critical factor for protecting tumor cells from T cell-mediated antitumor activity. Recent efforts have capitalized on the anti-N...
Source: Current Opinion in Immunology - December 6, 2012 Category: Allergy & Immunology Authors: Dimitroff CJ Tags: Curr Opin Immunol Source Type: research

The immunoproteasome in antigen processing and other immunological functions.
Abstract Treatment of cells with interferon-γ leads to the replacement of the constitutive catalytic proteasome subunits β1, β2, and β5 by the inducible subunits LMP2 (β1i), MECL-1 (β2i), and LMP7 (β5i), respectively, building the so-called immunoproteasome. The incorporation of these subunits is required for the production of numerous MHC class-I restricted T cell epitopes. Recently, new evidence for an involvement of the immunoproteasome in other facets of the immune response emerged. Investigations of autoimmune diseases in animal models and a genetic predisposition of β...
Source: Current Opinion in Immunology - December 6, 2012 Category: Allergy & Immunology Authors: Basler M, Kirk CJ, Groettrup M Tags: Curr Opin Immunol Source Type: research

Control of MHC II antigen presentation by ubiquitination.
Abstract MHC II antigen presentation is a critical pathway involved in the activation of the adaptive immune system. Tight regulatory controls are necessary to ensure appropriate MHC II antigen presentation. One mechanism for regulating this pathway is ubiquitination. Ubiquitination has been shown to play a critical role in fine-tuning the regulation of MHC II antigen presentation, with significant roles in antigen receptor internalisation and turnover of MHC II at the cell surface. The importance of ubiquitination is highlighted by bacterial pathogens that hijack the pathway to evade immune recognition. Understan...
Source: Current Opinion in Immunology - November 23, 2012 Category: Allergy & Immunology Authors: Moffat JM, Mintern JD, Villadangos JA Tags: Curr Opin Immunol Source Type: research