Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis.
Abstract CD4+ T cells have been long known to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the specific cell populations and states that drive the disease have been challenging to identify with low dimensional single cell data and bulk assays. The advent of high dimensional single cell technologies-like single cell RNA-seq or mass cytometry-has offered promise to defining key populations, but brings new methodological and statistical challenges. Recent single cell profiling studies have revealed a broad diversity of cell types among CD4+ T cells, identifying novel populations that a...
Source: Current Opinion in Immunology - September 6, 2017 Category: Allergy & Immunology Authors: Fonseka CY, Rao DA, Raychaudhuri S Tags: Curr Opin Immunol Source Type: research

Novel mechanisms in immune tolerance to allergens during natural allergen exposure and allergen-specific immunotherapy.
Abstract Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a clinical tolerance-inducing and immune tolerance-inducing therapy for allergic diseases and represents a potentially curative method of treatment. AIT functions through multiple mechanisms including early desensitization of basophils and mast cells, regulating T-cell and B-cell responses, changing antibody isotypes, and decreasing activation, mediator release and affected tissue migration of eosinophils, basophils, and mast cells. Similar molecular and cellular mechanisms have been observed in subcutaneous AIT, sublingual AIT...
Source: Current Opinion in Immunology - September 6, 2017 Category: Allergy & Immunology Authors: van de Veen W, Wirz OF, Globinska A, Akdis M Tags: Curr Opin Immunol Source Type: research

Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?
Abstract Psoriasis and atopic dermatitis (AD) are common T-cell mediated inflammatory diseases of the skin that can be treated by specific cytokine antagonists or more broad immunosuppressive drugs. The diseases are similar in that epidermal keratinocytes respond to T-cell derived cytokines by altering growth and differentiation responses, accounting for major parts of the overall disease phenotype. When studied across European-American populations, psoriasis and AD display differing T-cell polarity and different arrays of cytokines. Psoriasis is a disease largely driven by Th17 T-cells and associated IL-17 activa...
Source: Current Opinion in Immunology - September 1, 2017 Category: Allergy & Immunology Authors: Guttman-Yassky E, Krueger JG Tags: Curr Opin Immunol Source Type: research

Hemophagocytic syndrome: primary forms and predisposing conditions.
Abstract Hemophagocytic lymphohistiocytosis (HLH, also referred to a hemophagocytic syndrome) is a life-threatening condition in which uncontrolled activation of lymphocytes and macrophages, and thus the secretion of large amounts of inflammatory cytokines, leads to a severe hyperinflammatory state. Over the last few decades, researchers have characterized primary forms of HLH caused by genetic defects that impair lymphocytes' cytotoxic machinery. Other genetic causes of HLH not related to impaired cytotoxicity have also recently been identified. Furthermore, the so-called 'acquired' forms of HLH are encountered i...
Source: Current Opinion in Immunology - August 31, 2017 Category: Allergy & Immunology Authors: Sepulveda FE, de Saint Basile G Tags: Curr Opin Immunol Source Type: research

Check point inhibitors as therapies for infectious diseases.
Abstract The recent successes of immune check point targeting therapies in treating cancer patients has driven a resurgence of interest in targeting these pathways in chronically infected patients. While still in early stages, basic and clinical data suggest that blockade of CTLA-4 and PD-1 can be beneficial in the treatment of chronic HIV, HBV, and HCV infection, as well as other chronic maladies. Furthermore, novel inhibitory receptors such as Tim-3, LAG-3, and TIGIT are the potential next wave of check points that can be manipulated for the treatment of chronic infection. Blockade of these pathways influences m...
Source: Current Opinion in Immunology - August 30, 2017 Category: Allergy & Immunology Authors: Cox MA, Nechanitzky R, Mak TW Tags: Curr Opin Immunol Source Type: research

Immune development and environment: lessons from Amish and Hutterite children.
Abstract Children who grow up in traditional farm environments are protected from developing asthma and allergy. This 'farm effect' can be largely explained by the child's early life contact with farm animals, in particular cows, and their microbes. Our studies in Amish and Hutterite school children living on farms in the U.S. have further demonstrated that this protection is mediated through innate immune pathways. Although very similar with respect to ancestry and many lifestyle factors that are associated with asthma risk, Amish and Hutterites follow farming practices that are associated with profound differenc...
Source: Current Opinion in Immunology - August 24, 2017 Category: Allergy & Immunology Authors: Ober C, Sperling AI, von Mutius E, Vercelli D Tags: Curr Opin Immunol Source Type: research

Protective immunity against tuberculosis: what does it look like and how do we find it?
Abstract Progress towards the development of an effective vaccine against tuberculosis is hampered by the lack of correlative readouts of immune protection, coupled with our limited understanding of the immune mechanisms that determine disease progression versus containment. In this article we discuss the value of microbial readouts of bacterial fitness to probe the host immune environments and determine those host cell subsets that promote or control bacterial growth. Ultimately, we feel that these bacterial reporters will prove to be key in understanding the immune mechanisms underpinning disease outcome, and th...
Source: Current Opinion in Immunology - August 18, 2017 Category: Allergy & Immunology Authors: Huang L, Russell DG Tags: Curr Opin Immunol Source Type: research

The nonspecific face of adaptive immunity.
We describe the acquisition of non-antigen specific memory features by both innate and adaptive immune cells explaining these phenomena. We also focus on the different mechanisms (homeostatic or inflammatory cytokine-driven) that lead to acquisition of memory phenotype and functions by antigen-inexperienced T lymphocytes. We discuss the implications of these new concepts for host defense, auto-immunity and vaccination strategies. PMID: 28823577 [PubMed - as supplied by publisher] (Source: Current Opinion in Immunology)
Source: Current Opinion in Immunology - August 17, 2017 Category: Allergy & Immunology Authors: Muraille E, Goriely S Tags: Curr Opin Immunol Source Type: research

Immune mechanisms of respiratory viral infections in asthma.
Abstract The more severe pathology respiratory viral infections produce in asthma sufferers is a result of a dysregulated immune response. Excess type 2 inflammation is a well-described feature of virally induced asthma exacerbations, with growing evidence that production of antiviral interferons may also be impaired. However, the mechanisms underlying these are little understood. This review summarizes the current understanding and recent discoveries of the cellular and molecular events that follow viral infections in asthma. In particular, we discuss differences in viral sensing and intracellular signalling path...
Source: Current Opinion in Immunology - August 14, 2017 Category: Allergy & Immunology Authors: Farne HA, Johnston SL Tags: Curr Opin Immunol Source Type: research

Lessons from CTLA-4 deficiency and checkpoint inhibition.
Abstract CTLA-4 is a crucial negative regulator of immune responses. Absence of CTLA-4 in mice causes autoimmunity and lethal multiorgan lymphocytic infiltration and tissue destruction. Recently, heterozygous CTLA4 or biallelic LRBA mutations leading to functional CTLA-4 deficiency and autoimmunity have been discovered. LRBA was identified as a novel regulator of steady-state CTLA-4 protein levels in Tregs and activated T cells. CTLA-4 deficiency due to checkpoint blockade cancer immunotherapy has also been found to lead to autoimmune reactions. Studies investigating the variable efficacy and adverse autoimmune re...
Source: Current Opinion in Immunology - August 11, 2017 Category: Allergy & Immunology Authors: Lo B, Abdel-Motal UM Tags: Curr Opin Immunol Source Type: research

Cancer vaccines in the era of checkpoint blockade: the magic is in the adjuvant.
Abstract While T cell checkpoint blockade therapy of various cancers yields impressive clinical benefits, most patients are not cured. This is thought to result from insufficient spontaneous tumor-specific T cell responses, a situation that could be remedied with cancer-specific vaccination. Much work is underway to identify cancer-specific antigens, leaving open the question of how to formulate these antigens in a manner that provokes potent cancer-specific T cell responses. In this review I discuss paradigms guiding adjuvant development, and consider what may constitutes a clinically relevant T cell response. I ...
Source: Current Opinion in Immunology - August 11, 2017 Category: Allergy & Immunology Authors: Overwijk WW Tags: Curr Opin Immunol Source Type: research

Pathophysiology and immunological profile of myasthenia gravis and its subgroups.
Abstract Myasthenia gravis (MG) is an autoimmune antibody-mediated disease characterized by muscle weakness and fatigability. It is believed that the initial steps triggering humoral immunity in MG take place inside thymic tissue and thymoma. The immune response against one or several epitopes expressed on thymic tissue cells spills over to neuromuscular junction components sharing the same epitope causing humoral autoimmunity and antibody production. The main cause of MG is acetylcholine receptor antibodies. However, many other neuromuscular junction membrane protein targets, intracellular and extracellular prote...
Source: Current Opinion in Immunology - August 3, 2017 Category: Allergy & Immunology Authors: Romi F, Hong Y, Gilhus NE Tags: Curr Opin Immunol Source Type: research

Known unknowns: how might the persistent herpesvirome shape immunity and aging?
Abstract The microbial community that colonizes all living organisms is gaining appreciation for its contributions to both physiologic and pathogenic processes. The virome, a subset of the overall microbiome, large and diverse, including viruses that persistently inhabit host cells, endogenous viral elements genomically or epigenomically integrated into cells, and viruses that infect the other (bacterial, protozoan, fungal, and archaeal) microbiome phylla. These viruses live in the organism for its life, and therefore are to be considered part of the aging process experienced by the organism. This review considers...
Source: Current Opinion in Immunology - August 3, 2017 Category: Allergy & Immunology Authors: Nikolich-Zugich J, Goodrum F, Knox K, Smithey MJ Tags: Curr Opin Immunol Source Type: research

Organoid culture systems to study host-pathogen interactions.
Abstract Recent advances in host-microbe interaction studies in organoid cultures have shown great promise and have laid the foundation for much more refined future studies using these systems. Modeling of Zika virus (ZIKV) infection in cerebral organoids have helped us understand its association with microcephaly. Similarly, the pathogenesis of bacterial (Helicobacter pylori, Clostridium difficile) and viral (Norovirus, Rotaviruses) infections have been precisely dissected in organoid cultures. Additionally, direct associations between microbial colonization of tissues and diseases like cancer have also been deci...
Source: Current Opinion in Immunology - July 27, 2017 Category: Allergy & Immunology Authors: Dutta D, Clevers H Tags: Curr Opin Immunol Source Type: research

Four pathways of CD1 antigen presentation to T cells.
Abstract CD1a, CD1b, CD1c and CD1d proteins migrate through distinct subcellular compartments of antigen presenting cells and so can be considered to take four separate pathways leading to display of lipid antigens to T cell receptors. This review discusses the intersection of CD1 trafficking and lipid antigen loading mechanisms in cells, highlighting key controversies relating to CD1 gene expression, size mismatches between antigens and CD1 binding clefts and unexpected mechanisms of T cell receptor-based recognition. PMID: 28756303 [PubMed - as supplied by publisher] (Source: Current Opinion in Immunology)
Source: Current Opinion in Immunology - July 27, 2017 Category: Allergy & Immunology Authors: Moody DB, Cotton RN Tags: Curr Opin Immunol Source Type: research

Vaccines targeting helper T cells for cancer immunotherapy.
Abstract There are compelling arguments for designing cancer vaccines specifically to induce CD4(+) helper T cell responses. Recent studies highlight the crucial role of proliferating, activated effector memory Th1 CD4(+) T cells in effective antitumor immunity and reveal that CD4(+) T cells induce more durable immune-mediated tumor control than CD8(+) T cells. CD4(+) T cells promote antitumor immunity by numerous mechanisms including enhancing antigen presentation, co-stimulation, T cell homing, T cell activation, and effector function. These effects are mediated at sites of T cell priming and at the tumor microe...
Source: Current Opinion in Immunology - July 26, 2017 Category: Allergy & Immunology Authors: Melssen M, Slingluff CL Tags: Curr Opin Immunol Source Type: research

Towards an evidence based approach for the development of adjuvanted vaccines.
Abstract In the last two decades, several vaccines formulated with a new generation of adjuvants have been licensed or approved to target diseases such as influenza, hepatitis B, cervical cancer, and malaria. These new generation adjuvants appear to work by delivering a localized activation signal to the innate immune system, which in turn promotes antigen-specific adaptive immunity. Advances in understanding of the innate immune system together with high-throughput discovery of synthetic immune potentiators are now expanding the portfolio of new generation adjuvants available for evaluation. Meanwhile, omics and ...
Source: Current Opinion in Immunology - July 26, 2017 Category: Allergy & Immunology Authors: O'Hagan DT, Friedland LR, Hanon E, Didierlaurent AM Tags: Curr Opin Immunol Source Type: research

MAIT cells in infectious diseases.
Abstract In humans, MAIT cells represent the most abundant T cell subset reacting against bacteria. Their frequency in the blood is decreased in a large variety of infectious diseases of either bacterial or viral origin. MAIT cells accumulate at the site of bacterial infection and are protective in experimental infection models. Recent epidemiological evidence supports an implication of MAIT cells in protecting against tuberculosis. MAIT cells can be activated either through direct recognition of microbial ligands or by inflammatory cytokines such as IL-12 and IL-18. MAIT cells secrete IFN-γ, IL-17 and/or ot...
Source: Current Opinion in Immunology - July 24, 2017 Category: Allergy & Immunology Authors: Salou M, Franciszkiewicz K, Lantz O Tags: Curr Opin Immunol Source Type: research

TNF-receptor superfamily agonists as molecular adjuvants for cancer vaccines.
Abstract Cancer vaccines have offered unrequited hope as a mechanism for rapidly and potently eliciting a patient's immune system to counter tumors. Initial results from preclinical mouse models have not translated to substantial benefit to patients, suggesting that either the targets or the vaccination approach were inadequate. Recent innovations in antigen identification have spiked renewed interest vaccination technologies. This has coincided with a detailed molecular understanding of the coordinated steps in postactivation support of T cell proliferation, differentiation and survival, leading to the developmen...
Source: Current Opinion in Immunology - July 24, 2017 Category: Allergy & Immunology Authors: Bullock TN Tags: Curr Opin Immunol Source Type: research

Tuberculosis vaccines - perspectives from the NIH/NIAID Mycobacteria vaccine testing program.
Abstract The development of novel vaccine candidates against infections with Mycobacterium tuberculosis has highlighted our limited understanding of immune mechanisms required to kill M. tuberculosis. The induction of a Th1 immunity is vital, but new studies are required to identify other mechanisms that may be necessary. Novel vaccines formulations that invoke effector cells such as innate lymphoid cells may provide an environment that promote effector mechanisms including T cell and B cell mediated immunity. Identifying pathways associated with killing this highly successful infectious agent has become critical ...
Source: Current Opinion in Immunology - July 24, 2017 Category: Allergy & Immunology Authors: Izzo AA Tags: Curr Opin Immunol Source Type: research

Psoriasis: a mixed autoimmune and autoinflammatory disease.
Abstract In recent years marked progress has been made in our understanding of the critical biologic and immunologic pathways involved in psoriasis. Genetic studies have demonstrated that susceptibility to psoriasis involves components of both the adaptive and innate immune system and not surprisingly activation of both of these arms of the immune system is found in psoriatic skin. While adaptive immune responses predominate in chronic plaque psoriasis, innate and autoinflammatory responses dominate in pustular forms of psoriasis, with other clinical subtypes extending on a spectrum between plaque and pustular pso...
Source: Current Opinion in Immunology - July 21, 2017 Category: Allergy & Immunology Authors: Liang Y, Sarkar MK, Tsoi LC, Gudjonsson JE Tags: Curr Opin Immunol Source Type: research

The immunopathology of dengue and Zika virus infections.
Abstract A large proportion of the world's population live in areas with dengue virus (DENV) transmission resulting in tens of millions of symptomatic dengue cases each year. Serious complications following DENV infection occur more frequently in those suffering from a second or subsequent infection implicating virus-specific immunity as having a role in pathogenesis. In recent years outbreaks of the related Zika virus (ZIKV) have been associated with birth defects and neurological complications. As DENV and ZIKV share a viral vector sequential infections can occur. Given the sequence homology between the two viru...
Source: Current Opinion in Immunology - July 21, 2017 Category: Allergy & Immunology Authors: Culshaw A, Mongkolsapaya J, Screaton GR Tags: Curr Opin Immunol Source Type: research

Germinal center enhancement by extended antigen availability.
Abstract Vaccine elicitation of protective antibody responses has proved difficult for a number of important human pathogens, including HIV-1. The amount of somatic hypermutation associated with the development of broadly neutralizing antibodies against HIV has not been achieved using conventional immunization strategies. An underexplored aspect of vaccine design is modulation of antigen kinetics. Immunization strategies with extended antigen availability have recently been shown to enhance humoral responses. In this review, we explore the mechanisms through which sustained antigen availability can enhance germina...
Source: Current Opinion in Immunology - July 21, 2017 Category: Allergy & Immunology Authors: Cirelli KM, Crotty S Tags: Curr Opin Immunol Source Type: research

Old and new adjuvants.
Abstract Adjuvants have been deliberately added to vaccines since the 1920's when alum was discovered to boost antibody responses, leading to better protection. The first adjuvants were discovered by accident and were used in the safer but less immunogenic subunit vaccines, supposedly by providing an antigen depot to extend antigen presentation. Since that time, much has been discovered about how these adjuvants impact cells at the tissue site to activate innate immune responses, mobilize dendritic cells and drive adaptive immunity. New approaches to vaccine construction for infectious diseases that have so far no...
Source: Current Opinion in Immunology - July 19, 2017 Category: Allergy & Immunology Authors: McKee AS, Marrack P Tags: Curr Opin Immunol Source Type: research

CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination.
r L Abstract Vectors based on cytomegalovirus (CMV) represent a novel vaccine platform that maintains high frequencies of non-exhausted effector memory T cells in both CMV sero-positive and sero-negative individuals. In non-human primate models, CMV vectored vaccines provide unprecedented protection against simian immunodeficiency virus (SIV). Moreover, CMV vectors can be genetically altered to program highly diverse CD8+ T cell responses that differ in their epitope targeting including conventional, MHC-I restricted CD8+ T cells as well as unconventional CD8+ T cells restricted by MHC class II or non-polymorphic ...
Source: Current Opinion in Immunology - July 19, 2017 Category: Allergy & Immunology Authors: Früh K, Picker L Tags: Curr Opin Immunol Source Type: research

Cancer immunotherapy: moving forward with peptide T cell vaccines.
Abstract Recent advances in cancer immunology, such as the discovery of immune checkpoint inhibitors, have validated immune cells as potential key players for effective cancer treatment. The efficacy of these therapies seems to be codependent on a tumor-reactive T lymphocyte response. For many years, numerous attempts and strategies in developing vaccines to generate tumor-reactive T cells have yielded poor results in the clinic due to suboptimal immunogenicity and the inability to overcome an immunosuppressive tumor microenvironment. In this review, we summarize past and current advances in T cell vaccines and de...
Source: Current Opinion in Immunology - July 19, 2017 Category: Allergy & Immunology Authors: Kumai T, Fan A, Harabuchi Y, Celis E Tags: Curr Opin Immunol Source Type: research

Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines.
Abstract Development of therapeutic cancer vaccines has been hindered by the many pro-tumorigenic mechanisms at play in cancer patients that serve to suppress both antigen presenting cells and T cells. In face of these obstacles, cancer vaccines are most likely to promote anti-tumorigenic immune responses only when formulated with strong adjuvants, and in combination with new immune interventions designed to reverse immune suppression and exhaustion of T cells in the tumor microenvironment. Dendritic cells (DCs) are often termed 'nature's adjuvant' due to their exceptional capacity for initiating both innate and a...
Source: Current Opinion in Immunology - July 18, 2017 Category: Allergy & Immunology Authors: Saxena M, Bhardwaj N Tags: Curr Opin Immunol Source Type: research

No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines.
Abstract Development of non-infectious subunit vaccines is hampered by a slow pipeline of new adjuvants to replace or enhance alum in part because expectations of safety are high. Transient vaccine side effects are not clinical priorities because they cause no lasting harm and vaccine development has appropriately been focused on avoidance of serious adverse events. As a result, surprisingly little is known about the extent to which side effects caused by a vaccine's reactogencicity are predictive of successful immunization outcomes. Recent clinical studies of pertussis and human papillomavirus vaccines adjuvanted...
Source: Current Opinion in Immunology - July 17, 2017 Category: Allergy & Immunology Authors: Mitchell TC, Casella CR Tags: Curr Opin Immunol Source Type: research

Immunological tolerance as a barrier to protective HIV humoral immunity.
Abstract HIV-1 infection typically eludes antibody control by our immune system and is not yet prevented by a vaccine. While many viral features contribute to this immune evasion, broadly neutralizing antibodies (bnAbs) against HIV-1 are often autoreactive and it has been suggested that immunological tolerance may restrict a neutralizing antibody response. Indeed, recent Ig knockin mouse studies have shown that bnAb-expressing B cells are largely censored by central tolerance in the bone marrow. However, the contribution of peripheral tolerance in limiting the HIV antibody response by anergic and potentially prote...
Source: Current Opinion in Immunology - July 17, 2017 Category: Allergy & Immunology Authors: Schroeder KM, Agazio A, Torres RM Tags: Curr Opin Immunol Source Type: research

BCG - old workhorse, new skills.
Abstract Bacille Calmette-Guérin (BCG), the only tuberculosis (TB) vaccine in clinical practice, has limitations in efficacy, immunogenicity and safety. Much current TB vaccine research focuses on engineering live mycobacteria to interfere with phagosome biology and host intracellular pathways including apoptosis and autophagy, with candidates such as BCG Δzmp1, BCG ΔureC::hly, BCG::ESX-1(Mmar), Mtb ΔphoP ΔfadD26, Mtb ΔRD1 ΔpanCD and M. smegmatis Δesx-3::esx-3(Mtb) in the development pipeline. Correlates of protection in preclinical studies include increased central...
Source: Current Opinion in Immunology - July 15, 2017 Category: Allergy & Immunology Authors: Gengenbacher M, Nieuwenhuizen NE, Kaufmann S Tags: Curr Opin Immunol Source Type: research

Editorial Overview: Antigen Processing and Presentation; many fingers in many pies.
PMID: 28716443 [PubMed - as supplied by publisher] (Source: Current Opinion in Immunology)
Source: Current Opinion in Immunology - July 14, 2017 Category: Allergy & Immunology Authors: Cresswell P, Roche PA Tags: Curr Opin Immunol Source Type: research

Non-human primates as a model for understanding the mechanism of action of toll-like receptor-based vaccine adjuvants.
te; K Abstract While transgenic mouse models are powerful for understanding how the immune system is manipulated by vaccines, they cannot fully recapitulate the characteristics of the innate immune responses leading to adaptive immunity after vaccination in humans. Outbred non-human primates are far more representative models of human vaccine responses as there is high degree of similarities in immune cell subset distributions, receptor expression (including toll-like receptors; TLRs), and immune cell functions, in addition to modeling doses and injection sites more accurately. Vaccine adjuvants targeting TLRs hav...
Source: Current Opinion in Immunology - July 14, 2017 Category: Allergy & Immunology Authors: Thompson EA, Loré K Tags: Curr Opin Immunol Source Type: research

Editorial overview: Metabolism of T cells: integrating nutrients, signals, and cell fate.
PMID: 28684058 [PubMed - as supplied by publisher] (Source: Current Opinion in Immunology)
Source: Current Opinion in Immunology - July 3, 2017 Category: Allergy & Immunology Authors: MacIver NJ, Rathmell JC Tags: Curr Opin Immunol Source Type: research

Reviewing the impact of lipid synthetic flux on Th17 function.
Abstract CD4+ T helper 17 cells (Th17) acquire specific effector functions in response to activation and instructional signals. Accumulating evidence indicates that specific cellular lipid metabolic pathways play essential roles in regulating the differentiation and function of Th17 cells. Mechanistic studies reveal that metabolic fluxes through both the cholesterol and long chain fatty acid biosynthetic pathways are important in controlling RORγ transcriptional activity through their ability to generate lipid ligands of RORγ. Genetic and pharmacologic studies demonstrate that altering the flux through...
Source: Current Opinion in Immunology - June 29, 2017 Category: Allergy & Immunology Authors: Kidani Y, Bensinger SJ Tags: Curr Opin Immunol Source Type: research

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis.
Abstract In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to ...
Source: Current Opinion in Immunology - May 21, 2017 Category: Allergy & Immunology Authors: Weyand CM, Zeisbrich M, Goronzy JJ Tags: Curr Opin Immunol Source Type: research

mTOR signaling in the differentiation and function of regulatory and effector T cells.
Abstract The mechanistic target of rapamycin (mTOR) signaling pathway integrates environmental signals and cellular metabolism to regulate T cell development, activation and differentiation. Recent studies reveal the importance of exquisite control of mTOR activity for proper T cell function, and detailed molecular mechanisms that regulate mTOR signaling in different T cell subsets. Here, we review the latest advances in our understanding of the mTOR pathway and its regulation in the differentiation and function of regulatory T cells and effector T cells. PMID: 28535458 [PubMed - as supplied by publisher] (So...
Source: Current Opinion in Immunology - May 20, 2017 Category: Allergy & Immunology Authors: Zeng H, Chi H Tags: Curr Opin Immunol Source Type: research

The ongoing saga of the mechanism(s) of MHC class I-restricted cross-presentation.
Abstract Cross-presentation is an MHC-I antigen processing pathway that results in the presentation of peptides from exogenous viral, bacterial, parasitic, and tumor antigens and ultimately leads to priming of naïve CD8(+) T cells. This process involves several cellular compartments and multiple components. Successful generation of MHC-I-peptide complexes requires that these components act together in a coordinated fashion. We discuss recent findings on the source of MHC-I, the role of the TAP transporter, the importance of intracellular trafficking events, mechanisms of antigen access the cytosol, and how in...
Source: Current Opinion in Immunology - May 18, 2017 Category: Allergy & Immunology Authors: Grotzke JE, Sengupta D, Lu Q, Cresswell P Tags: Curr Opin Immunol Source Type: research

Properties of the tapasin homologue TAPBPR.
Abstract The presentation of antigenic peptides by MHC class I molecules plays a vital role in generating T cell responses against infection and cancer. Over the last two decades the central role of tapasin as a peptide editor that influences the loading and optimisation of peptides onto MHC class I molecules has been extensively characterised. Recently, it has become evident that the tapasin-related protein, TAPBPR, functions as a second peptide editor which influences the peptides displayed by MHC class I molecules. Here, we review the discovery of TAPBPR and current understanding of this novel protein in relati...
Source: Current Opinion in Immunology - May 18, 2017 Category: Allergy & Immunology Authors: Neerincx A, Boyle LH Tags: Curr Opin Immunol Source Type: research

Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease.
Abstract It is becoming increasingly clear that metabolic reprogramming plays a critical role in T cell activation, differentiation and function. To this end, cellular metabolism not only meets the energetic demands of T cells but also provides critical substrates for their growth and function. Furthermore, metabolites themselves are emerging as key regulators of immune responses. As the details of how metabolic reprogramming regulates immune function are revealed, new potential targets for modulating immune responses have emerged. Indeed, the distinct metabolic demands of different T cell subsets make them exquis...
Source: Current Opinion in Immunology - May 15, 2017 Category: Allergy & Immunology Authors: Patel CH, Powell JD Tags: Curr Opin Immunol Source Type: research

Unusual antigen presentation offers new insight into HIV vaccine design.
Abstract Recent findings with a rhesus monkey cytomegalovirus based simian immunodeficiency virus vaccine have identified strong CD8+ T cell responses that are restricted by MHC-E. Also mycobacteria specific CD8+ T cells, that are MHC-E restricted, have been identified. MHC-E therefore can present a wide range of epitope peptides to CD8+ T cells, alongside its well defined role in presenting a conserved MHC-class I signal peptide to the NKG2A/C-CD94 receptor on natural killer cells. Here we explore the antigen processing pathways involved in these atypical T cell responses. PMID: 28505602 [PubMed - as supplie...
Source: Current Opinion in Immunology - May 12, 2017 Category: Allergy & Immunology Authors: McMichael AJ, Picker LJ Tags: Curr Opin Immunol Source Type: research

MAIT cells and MR1-antigen recognition.
Abstract Mucosal-associated invariant T cells (MAIT cells) are innate-like T cells that recognise antigens presented by the monomorphic MHC-I related molecule, MR1. Distinct from the conventional MHC-restricted T cell system, MR1 presents small-molecule precursors, derived from microbial biosynthesis of riboflavin, to activate the innate MAIT cell effector potential. Recent data demonstrates how: vitamin B precursors modulate intracellular trafficking of MR1 and impact on MAIT cell development; variation in the MAIT cell antigen receptor sequence impacts MR1-antigen recognition; and most notably, how MR1 can captu...
Source: Current Opinion in Immunology - May 8, 2017 Category: Allergy & Immunology Authors: Keller AN, Corbett AJ, Wubben JM, McCluskey J, Rossjohn J Tags: Curr Opin Immunol Source Type: research

Characterizing neoantigens for personalized cancer immunotherapy.
Abstract Somatic mutations can generate neoantigens that are presented on MHC molecules and drive effective T cells responses against cancer. Mutation load in cancer patients predicts response to immune checkpoint blockade therapy. Additionally, vaccination targeting neoantigens controls established tumor growth in preclinical models. These recent findings led to a renewed interest in the field of cancer vaccines and the development of antigen-targeted cancer immunotherapies. However, targeting neoantigens is challenging, as most mutations are unique to each cancer patient. In addition, only a small fraction of th...
Source: Current Opinion in Immunology - May 4, 2017 Category: Allergy & Immunology Authors: Capietto AH, Jhunjhunwala S, Delamarre L Tags: Curr Opin Immunol Source Type: research

Antigen processing and presentation in the thymus: implications for T cell repertoire selection.
Abstract The processing and presentation of major histocompatibility complex (MHC)-associated antigens depend on the intracellular digestion of self- and nonself-proteins, the loading of digested peptides onto MHC molecules, and the traffic of peptide-MHC complexes to plasma membrane surface for display to interacting T cells. Recent studies have revealed unique machineries for antigen processing and presentation in thymic antigen-presenting cells that display self-antigens to developing thymocytes for the formation of functionally competent yet self-tolerant T cell repertoire. Here, we briefly summarize those mac...
Source: Current Opinion in Immunology - May 3, 2017 Category: Allergy & Immunology Authors: Kondo K, Takada K, Takahama Y Tags: Curr Opin Immunol Source Type: research

The role of AMPK in T cell metabolism and function.
Abstract The AMP-activated protein kinase (AMPK) is a key metabolic regulator that both senses changes in cellular energy levels and activates pathways to maintain cellular energy balance. AMPK achieves this by stimulating catabolic pathways that generate ATP and inhibiting biological pathways that consume ATP consumption. Recent work has established that AMPK is activated in T cells by both immunological and environmental stimuli, and plays an important role in T cell metabolism, in part by controlling T cell 'metabolic plasticity'. Recent data have revealed distinct functions for AMPK in T cells, including effec...
Source: Current Opinion in Immunology - April 28, 2017 Category: Allergy & Immunology Authors: Ma EH, Poffenberger MC, Wong AH, Jones RG Tags: Curr Opin Immunol Source Type: research

Reenergizing T cell anti-tumor immunity by harnessing immunometabolic checkpoints and machineries.
Abstract T cells patrol our bodies preventing pathogenic infections and malignant cell outgrowth. However, T cells must be properly controlled because aberrant or persistent T cell responses can damage tissues and contribute to autoimmune diseases and other chronic inflammatory diseases including metabolic syndrome. One regulatory mechanism utilized in immune cells is immunometabolic regulation, which ensures immune cells properly respond to systemic and peripheral metabolic cues. Recent work has suggested that deregulated metabolism in tumor cells creates a microenvironmental barrier for mounting effective anti-t...
Source: Current Opinion in Immunology - April 27, 2017 Category: Allergy & Immunology Authors: Ho PC, Kaech SM Tags: Curr Opin Immunol Source Type: research

Unique features in the presentation of insulin epitopes in autoimmune diabetes: an update.
Abstract Although an autoimmune disease involves diverse self-antigens, the initiation stage may require recognition of a limited number. This concept is verified in the non-obese diabetic (NOD) mouse model of autoimmune diabetes, in which strong evidence points to insulin as the prime antigen. The NOD mouse bears the I-A(g7) class II-MHC molecules (MHCII) that share common biochemical features and peptidome selection with the human diabetes-susceptible HLA-DQ8. Furthermore, both NOD mice and patients with type 1 diabetes (T1D) display an early appearance of insulin autoantibodies (IAAs) and subsequent insulin-rea...
Source: Current Opinion in Immunology - April 26, 2017 Category: Allergy & Immunology Authors: Wan X, Unanue ER Tags: Curr Opin Immunol Source Type: research

What chickens might tell us about the MHC class II system.
Abstract Almost all knowledge about the structure and function of MHC class II molecules outside of mammals comes from work with chickens. Most of the genes implicated in the class II system are present in chickens, so it is likely that the machinery of antigen processing and peptide-loading is similar to mammals. However, there is only one isotype (lineage) of classical class II genes, with one monomorphic DR-like BLA gene and two polymorphic BLB genes, located near one DMA and two DMB genes. The DMB2 and BLB2 genes are widely expressed at high levels, whereas the DMB1 and BLB1 genes are only expressed at highest...
Source: Current Opinion in Immunology - April 20, 2017 Category: Allergy & Immunology Authors: Parker A, Kaufman J Tags: Curr Opin Immunol Source Type: research

Metabolic reprograming of anti-tumor immunity.
Abstract Immunotherapies designed to trigger T cell destruction of tumor cells can result in sustained and complete responses in patients whose cancers were resistant to available treatment options. Evidence suggests that powering the T cell response - how T cells generate energy - plays an important role in their effectiveness. Furthermore the metabolism of T cells can be modulated to improve their anti-cancer activities. In this review, we will discuss the key metabolic properties of anti-cancer T cells, along with potential strategies to enhance immunotherapy through the modulation of T cell metabolism. PM...
Source: Current Opinion in Immunology - April 13, 2017 Category: Allergy & Immunology Authors: Sukumar M, Kishton RJ, Restifo NP Tags: Curr Opin Immunol Source Type: research

Memory B cells: total recall.
Abstract Immunological memory is a cornerstone of adaptive immune responses in higher vertebrates. The remarkable ability to generate memory cells following Ag exposure, in the context of natural infection or immunization, provides long-lived protection against infectious diseases, often for the hosts' lifetime. Indeed, the generation of memory B cells and long-lived plasma cells underpins the success of most vaccines. The concept of immunological memory is not new-it was first proposed nearly 2500 years ago. While our understanding of the complexities of humoral and cell-mediated memory continues to evolve, impor...
Source: Current Opinion in Immunology - March 28, 2017 Category: Allergy & Immunology Authors: Phan TG, Tangye SG Tags: Curr Opin Immunol Source Type: research

Obesity altered T cell metabolism and the response to infection.
Abstract An epidemic of obesity over the past three decades increases the risk of chronic and infectious diseases for adults and children alike. Within the past few years, obesity has been shown to impair the adaptive immune response to infection through alterations in T cell functioning. Growing evidence suggests that perturbations in T cell metabolism drives this stunted immune response, stemming from nutrient, hormone and adipokine dysregulation in the obese. In this review, recent findings in the fields of obesity and T cell mediated immunity demonstrate a unique relationship between altered mechanisms of T ce...
Source: Current Opinion in Immunology - March 27, 2017 Category: Allergy & Immunology Authors: Green WD, Beck MA Tags: Curr Opin Immunol Source Type: research