Interaction Of Antigen-presenting Cells Research Articles

The Effect of Static Magnetic Fields of Different Strengths and Polarities on Cytokine Production by Human Lymphocytes In Vitro.

In contrast to electromagnetic fields, static magnetic fields (SMFs) have not been extensively studied in terms of their potential health consequences. Although upward- and downward-oriented magnetic poles may cause various biological effects, only the pole with the upward orientation has been mainly investigated. Considering that the interaction of antigen-presenting cells (APCs) and T lymphocytes is crucial to trigger an immune response, we assessed the effect of long-term exposure of human T lymphocytes and dendritic cells (DCs) to moderate strength SMFs of different orientations focusing on the cytokine profile of activated T cells. Cultures of allogenic T lymphocytes and DCs (immature and matured by TLR3 and TLR7 agonists) were continuously exposed to four SMFs. The intensity of the applied field was 1 militesla (mT) or 56 mT of the upward- and downward-oriented pole of the SMF. Cell culture supernatants were assayed for IFN-γ, IL-4, IL-17, TNF-α, TNF-β, IL-1 β, IL-6, IL-8, and IL-10 by ELISA or flow cytometry. The upward-oriented 56 mT SMF significantly increased the release of IFN-γ and TNF-β (both p < 0.05) in the cell culture supernatants of T cells and immature DCs. In contrast, the same cultures exposed to the upward-oriented 1 mT SMF showed significantly elevated levels of IL-17 (p < 0.05). The levels of IL-4, TNF-α, IL-1 β, IL-6, IL-8, and IL-10 were not affected by the upward-oriented SMF. The downward-oriented 56 mT SMF increased TNF-α release when T cells were stimulated with mature DCs. The production of other cytokines was unchanged by the downward-oriented SMF. These findings demonstrate for the first time different in vitro biological effects of upward- and downward-oriented static magnetic fields on the cytokine production of T cells activated by DCs, helping to better understand SMF effects on the immune system and suggesting that the selective SMF effect on the immune response could have potential therapeutic effects in different immune-mediated disorders.

Mathematical Model to Predict Polyclonal T-Cell-Dependent Antibody Synthesis Responses

Mathematical models are becoming indispensable tools to explore the complexities of biological systems at cellular levels. We present a model to explore the baseline immune cell interactions for in vitro polyclonal antibody synthesis via B-cells regulated by helper and regulatory T-cells. The model incorporates interactions of antigen-presenting cells, T-cells, regulatory T-cells, and B-cells with each other and predicts time-dependent trajectories of these cells and antibody synthesis stimulated by pokeweed mitogen. We used an ordinary differential equation-based approach to simulate the dynamic changes in the cells and cytokines numbers due to the cellular and humoral response to pokeweed mitogen stimulation. The parameters of the ordinary differential equations model are determined to yield a normal immune response as observed in the pokeweed mitogen-stimulated in vitro antibody synthesis via normal T, B, and antigen-presenting cells. The dose effects of antigen load and basal values of regulatory T-cells on the profiles of various immune response variables are also evaluated.

A tessellated lymphoid network provides whole-body T cell surveillance in zebrafish

Homeostatic trafficking to lymph nodes allows T cells to efficiently survey the host for cognate antigen. Nonmammalian jawed vertebrates lack lymph nodes but maintain diverse T cell pools. Here, we exploit invivo imaging of transparent zebrafish to investigate how T cells organize and survey for antigen in an animal devoid of lymph nodes. We find that naïve-like T cells in zebrafish organize into a previously undescribed whole-body lymphoid network that supports streaming migration and coordinated trafficking through the host. This network has the cellular hallmarks of a mammalian lymph node, including naïve T cells and CCR7-ligand expressing nonhematopoietic cells, and facilitates rapid collective migration. During infection, T cells transition to a random walk that supports antigen-presenting cell interactions and subsequent activation. Our results reveal that T cells can toggle between collective migration and individual random walks to prioritize either large-scale trafficking or antigen search insitu. This lymphoid network thus facilitates whole-body T cell trafficking and antigen surveillance in the absence of a lymph node system.

Podocalyxin Expressed in Antigen Presenting Cells Promotes Interaction With T Cells and Alters Centrosome Translocation to the Contact Site.

Podocalyxin (PODXL), a cell surface sialomucin expressed in diverse types of normal and malignant cells, mediates cellular adhesion to extracellular matrix and cell-to-cell interaction. A previous study reported the expression of PODXL protein on monocytes undergoing macrophage differentiation, yet the expression of this molecule in other antigen presenting cells (APCs) and its function in the immune system still remain undetermined. In this study, we report that PODXL is expressed in human monocyte-derived immature dendritic cells at both the mRNA and protein levels. Following dendritric cells maturation using pro-inflammatory stimuli, PODXL expression level decreased substantially. Furthermore, we found that PODXL expression is positively regulated by IL-4 through MEK/ERK and JAK3/STAT6 signaling pathways. Our results revealed a polarized distribution of PODXL during the interaction of APCs with CD4+ T cells, partially colocalizing with F-actin. Notably, PODXL overexpression in APCs promoted their interaction with CD4+ T cells and CD8+ T cells and decreased the expression of MHC-I, MHC-II, and the costimulatory molecule CD86. In addition, PODXL reduced the translocation of CD4+ T-cell centrosome toward the APC-contact site. These findings suggest a regulatory role for PODXL expressed by APCs in immune responses, thus representing a potential target for therapeutic blockade in infection and cancer.

Antigen-Presenting Cells and T Cells Interact in a Specific Area of the Intestinal Mucosa Defined by the Ccl25-Ccr9 Axis in Medaka.

Organized intestinal mucosal immune response appears to be restricted to tetrapods. In teleost fish, there is no evidence for the existence of a particular intestinal region that facilitates the interaction of antigen-presenting cells (APCs) and T cells, such as secondary lymphoid organs. Indeed, despite their importance in the defense against pathogens, the location and manner of APC-T cell interaction within the fish gut is unknown. Here, using non-invasive live imaging of newly developed transgenic reporter lines, we addressed the spatial organization and behavior of APCs and T cells in the intestine of medaka fish both during homeostasis and inflammation. We report that Ccr9a+ T cells are recruited to a band in the lamina propria next to the muscularis mucosa in which Ccl25-expressing cells are present. Ccr9a+ T cells contact APCs for several minutes, in a process mediated by connexin 43. This type of interaction was observed in homeostasis and inflammation, with the interaction being longer and more frequent during inflammation. Thus, our results demonstrate that the mucosal immune response in the intestine of medaka is organized and endowed with a specific region with specialized microenvironment and function.

Autoimmunity in motion: Mechanisms of immune regulation and destruction revealed by in vivo imaging.

Autoimmunity arises when mechanisms of immune tolerance fail. Here we discuss mechanisms of T cell activation and tolerance and the dynamics of the autoimmune response at the site of disease. Live imaging of autoimmunity provides the ability to analyze immune cell dynamics at the single-cell level within the complex intact environment where disease occurs. These analyses have revealed mechanisms of T cell activation and tolerance in the lymph nodes, mechanisms of T cell entry into sites of autoimmune disease, and mechanisms leading to pathogenesis or protection in the autoimmune lesions. The overarching conclusions point to stable versus transient T cell antigen presenting cell interactions dictating the balance between T cell activation and tolerance, and T cell restimulation as a driver of pathogenesis at the site of autoimmunity. Findings from models of multiple sclerosis and type 1 diabetes are highlighted, however, the results have implications for basic mechanisms of T cell regulation during immune responses, tumor immunity, and autoimmunity.

IMMU-52. EFFECTS OF IMMUNE CHECKPOINT BLOCKADE ON ANTIGEN-SPECIFIC CD8+ T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY

Abstract BACKGROUND Adoptive T-cell therapies have been successfully used as treatment for patients diagnosed with advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors have shown to rescue immune anti-tumor responses. We hypothesized that in-vitro checkpoint blockade during T-cell stimulation and expansion with RNA-pulsed dendritic cells may enhance the activity of antigen-specific T-cells and improve the efficacy of ACT platforms. METHODS Human PBMCs were isolated from CMV seropositive donors to generate DCs and pulsed them with CMVpp65-mRNA to educate T-cells in co-culture for 15-days. We targeted pp65 antigen which is ubiquitously expressed by glioblastoma cells. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3 and anti-PD1+Tim3). IL2 was added every 3 days as well as the blockade antibodies. Immunephenotyping was performed on Day-0 and Day-15. Polyfunctional antigen specific responses were evaluated upon rechallenge with CMVpp65 peptides. RESULTS CMVpp65 activated CD8+ T-cells upregulate Lag3 and Tim3 (p= &amp;lt; 0.0001). Tim3 blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+pp65Tetramer+ central memory, effector memory, and TEMRA T-cells. This latter T-cell subset uniquely maintain double-positive Tim3/Lag3 expression after blockade. In contrast, PD-1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-g secretion was reduced in T-cells treated with Tim3 blockade in a dose-dependent manner (p= 0.004). CONCLUSION In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking Tim3 axis during T-cell antigen presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.

Approaches to inducing antigen-specific immune tolerance in allergy and autoimmunity: Focus on antigen-presenting cells and extracellular vesicles.

Increasing prevalence of allergic and autoimmune diseases urges clinicians and researchers to search for new and efficient treatments. Strategies that activate antigen-specific immune tolerance and simultaneously maintain immune reactivity to all other antigens deserve special attention. Accordingly, antigen-presenting cells (APCs) seem to be the best suited for orchestrating these mechanisms by directing T cell immune responses towards a tolerant subtype. Recent advances in understanding cell-to-cell communication via extracellular vesicles (EVs) make the latter promising candidates for reprogramming APCs towards a tolerant phenotype, and for mediating tolerogenic APC function. Thus, comprehensive studies have been undertaken to describe the interactions of APCs and EVs naturally occurring during immune tolerance induction, as well as to develop EV-based manoeuvres enabling the induction of immune tolerance in an antigen-specific manner. In this review, we summarize the findings of relevant studies, with a special emphasis on future perspectives on their translation to clinical practice.

MicroRNA-155 Controls T Helper Cell Activation During Viral Infection.

MicroRNA (miR) 155 has been implicated in the regulation of innate and adaptive immunity as well as autoimmune processes. Importantly, it has been shown to regulate several antiviral responses, but its contribution to the immune response against cytopathic viruses such as vesicular stomatitis virus (VSV) infections is not known. Using transgenic/recombinant VSV expressing ovalbumin, we show that miR-155 is crucially involved in regulating the T helper cell response against this virus. Our experiments indicate that miR-155 in CD4+ T cells controls their activation, proliferation, and cytokine production in vitro and in vivo upon immunization with OVA as well as during VSV viral infection. Using intravital multiphoton microscopy we analyzed the interaction of antigen presenting cells (APCs) and T cells after OVA immunization and found impaired complex formation when using miR-155 deficient CD4+ T cells compared to wildtype CD4+ T cells ex vivo. In contrast, miR-155 was dispensable for the maturation of myeloid APCs and for their T cell stimulatory capacity. Our data provide the first evidence that miR-155 is required for efficient CD4+ T cell activation during anti-viral defense by allowing robust APC-T cell interaction required for activation and cytokine production of virus specific T cells.

PB1982 AN IN VITRO STUDY OF THE INTERACTIONS BETWEEN THE CELL BASED CANCER VACCINE DCP‐001 AND ANTIGEN PRESENTING CELLS

Background:DCP‐001 is a whole cell‐based vaccine derived from the DCOne® human myelomonocytic leukemic cell line. DCOne cells endogenously express known and unknown tumour‐associated antigens. In the DCP‐001 manufacturing process, DCOne cells are differentiated and matured into cells with a mature dendritic cell phenotype. A phase I clinical trial demonstrated that the vaccine is safe and induces local and systemic cellular and humoral immune responses. DCP‐001 is currently studied in an international Phase II trial in AML patients ineligible for HSCT.Aims:To study the role of the interaction of whole cell‐based vaccine DCP‐001 with host immune cells.Methods:DCP‐001 and antigen presenting cell interaction studies were performed using flow cytometry and confocal microscopy. Cytokine/chemokine analyses were performed using luminex technology.Results:The strong immunogenicity of DCP‐001 is demonstrated by the broad range of chemokines and pro‐inflammatory cytokines released upon co‐culture of DCP‐001 with human peripheral blood mononuclear cells. Using different methods, we further demonstrate that antigen presenting cells efficiently process DCP‐001 through phagocytosis.Summary/Conclusion:These in vitro data suggest that in vivo, upon intradermal injection, DCP‐001 induces a strong inflammatory response, and is ingested by both resident as well as attracted host's APC, which subsequently prime tumour‐reactive T cells.

Enhanced antigen presenting and T cell functions during late-phase allergic responses in the lung.

Allergic inflammation is a common feature of asthma and may contribute to both development and perpetuation of disease. The interaction of antigen-presenting cells (APC) with sensitized helper T lymphocytes (TC) producing Th2 cytokines may determine the inflammatory response. Recruitment of APC and TC to the lung during allergic responses has been demonstrated, but functional studies in humans have been limited. This study examined the function of APC and TC accumulating at sites of inflammation after segmental allergen challenge (SAC). Fifteen allergic patients underwent SAC, and cells from bronchoalveolar lavage (BAL) were collected after 24 hours. APC and TC from the blood and BAL were purified based on expression of the monocyte marker, CD14; the plasmacytoid dendritic cell (pDC) marker, BDCA4, identifying neuropilin-1 (NRP1); and the helper T cell marker, CD4. Functional activity was assessed using allergen-induced T cell proliferation. Flow cytometry identified cells expressing CD14 and NRP1. SAC resulted in a 12-fold increase in mononuclear cells having the morphologic appearance of blood monocytes. Most of these cells co-expressed CD14 and NRP1. After saline challenge, BAL mononuclear cells demonstrated little APC function. Following SAC, BAL mononuclear cells showed function equal to pDC from blood and greater than blood monocytes. Purified NRP1+ cells from BAL had even greater function than pDC cells from blood (P = .008). Using consistent sources of APC, enhanced proliferation of TC from lung compared to blood was also demonstrated (P = .002). The marked increase in APC function for allergen-specific TC proliferation during allergic inflammation is largely due to the recruitment of monocytes and dendritic cells. There is also an enhanced response in the lung TC population, consistent with recruitment of allergen-specific T cells. Interactions between recruited APC and TC may occur as an early event promoting allergic airway inflammation.

Systematic Screening of Chemokines to Identify Candidates to Model and Create Ectopic Lymph Node Structures for Cancer Immunotherapy

The induction of ectopic lymph node structures (ELNs) holds great promise to augment immunotherapy against multiple cancers including metastatic melanoma, in which ELN formation has been associated with a unique immune-related gene expression signature composed of distinct chemokines. To investigate the therapeutic potential of ELNs induction, preclinical models of ELNs are needed for interrogation of these chemokines. Computational models provide a non-invasive, cost-effective method to investigate leukocyte trafficking in the tumor microenvironment, but parameterizing such models is difficult due to differing assay conditions and contexts among the literature. To better achieve this, we systematically performed microchemotaxis assays on purified immune subsets including human pan-T cells, CD4+ T cells, CD8+ T cells, B cells, and NK cells, with 49 recombinant chemokines using a singular technique, and standardized conditions resulting in a dataset representing 238 assays. We then outline a groundwork computational model that can simulate cellular migration in the tumor microenvironment in response to a chemoattractant gradient created from stromal, lymphoid, or antigen presenting cell interactions. The resulting model can then be parameterized with standardized data, such as the dataset presented here, and demonstrates how a computational approach can help elucidate developing ELNs and their impact on tumor progression.

A novel intracellular pool of LFA-1 is critical for asymmetric CD8+ T cell activation and differentiation.

The integrin lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) is a key T cell adhesion receptor that mediates stable interactions with antigen-presenting cell (APC), as well as chemokine-mediated migration. Using our newly generated CD11a-mYFP knock-in mice, we discovered that naive CD8+ T cells reserve a significant intracellular pool of LFA-1 in the uropod during migration. Intracellular LFA-1 quickly translocated to the cell surface with antigenic stimulus. Importantly, the redistribution of intracellular LFA-1 at the contact with APC was maintained during cell division and led to an unequal inheritance of LFA-1 in divided T cells. The daughter CD8+ T cells with disparate LFA-1 expression showed different patterns of migration on ICAM-1, APC interactions, and tissue retention, as well as altered effector functions. In addition, we identified Rab27 as an important regulator of the intracellular LFA-1 translocation. Collectively, our data demonstrate that an intracellular pool of LFA-1 in naive CD8+ T cells plays a key role in T cell activation and differentiation.

ProInflam: a webserver for the prediction of proinflammatory antigenicity of peptides and proteins.

BackgroundProinflammatory immune response involves a complex series of molecular events leading to inflammatory reaction at a site, which enables host to combat plurality of infectious agents. It can be initiated by specific stimuli such as viral, bacterial, parasitic or allergenic antigens, or by non-specific stimuli such as LPS. On counter with such antigens, the complex interaction of antigen presenting cells, T cells and inflammatory mediators like IL1α, IL1β, TNFα, IL12, IL18 and IL23 lead to proinflammatory immune response and further clearance of infection. In this study, we have tried to establish a relation between amino acid sequence of antigen and induction of proinflammatory response.ResultsA total of 729 experimentally-validated proinflammatory and 171 non-proinflammatory epitopes were obtained from IEDB database. The A, F, I, L and V amino acids and AF, FA, FF, PF, IV, IN dipeptides were observed as preferred residues in proinflammatory epitopes. Using the compositional and motif-based features of proinflammatory and non-proinflammatory epitopes, we have developed machine learning-based models for prediction of proinflammatory response of peptides. The hybrid of motifs and dipeptide-based features displayed best performance with MCC = 0.58 and an accuracy of 87.6 %.ConclusionThe amino acid sequence-based features of peptides were used to develop a machine learning-based prediction tool for the prediction of proinflammatory epitopes. This is a unique tool for the computational identification of proinflammatory peptide antigen/candidates and provides leads for experimental validations. The prediction model and tools for epitope mapping and similarity search are provided as a comprehensive web server which is freely available at http://metagenomics.iiserb.ac.in/proinflam/ and http://metabiosys.iiserb.ac.in/proinflam/.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0928-3) contains supplementary material, which is available to authorized users.

Immunotherapy in head and neck cancer

The physiological immune response to malignant cells is based on the interaction of antigen-presenting cells, such as dendritic cells and macrophages, with Tand Blymphocytes. CD8(+) effector and natural killer cells are primarily responsible for tumor cell lysis. Tumor cells exploit several mechanisms to influence the body's immune system and promote development and progress of solid head and neck malignancies. Via regulatory Tcells, myeloid-derived suppressor cells, tumor-associated macrophages, and cancer-associated fibroblasts, tumor cells promote development of suppressive signaling pathways that enable tumor progression. Novel immune therapeutics aim to influence these signaling pathways. Current studies are investigating agents which influence immune-stimulating or immune-suppressive cytokines, as well as drug-based Toll-like receptor activation and vaccination in head and neck cancer. Development of monoclonal antibodies allows for direct and highly specific binding of therapeutics to cell receptors - recently discovered immune checkpoint receptors are particularly intriguing targets. Monoclonal antibodies directed specifically toward Tcell-stimulating receptors such as CD28 and CD134, or immunosuppressive receptors CTLA-4 and PD-1, are currently under investigation and have shown promising results.

In vitro and in vivo imaging of initial B-T-cell interactions in the setting of B-cell based cancer immunotherapy

There has been a growing interest in the use of B cells for cancer vaccines, since they have yielded promising results in preclinical animal models. Contrary to dendritic cells (DCs), we know little about the migration behavior of B cells in vivo. Therefore, we investigated the interactions between CD40-activated B (CD40B) cells and cytotoxic T cells in vitro and the migration behavior of CD40B cells in vivo. Dynamic interactions of human antigen-presenting cells (APCs) and T cells were observed by time-lapse video microscopy. The migratory and chemoattractant potential of CD40B cells was analyzed in vitro and in vivo using flow cytometry, standard transwell migration assays, and imaging of fluorescently labeled murine CD40B cells. Murine CD40B cells show migratory features similar to human CD40B cells. They express important lymph node homing receptors which were functional and induced chemotaxis of T cells in vitro. Striking differences were observed with regard to interactions of human APCs with T cells. CD40B cells differ from DCs by displaying a rapid migratory pattern undergoing highly dynamic, short-lived and sequential interactions with T cells. In vivo, CD40B cells are home to the secondary lymphoid organs where they accumulate in the B cell zone before traveling to the B/T cell boundary. Moreover, intravenous (i.v.) administration of murine CD40B cells induced an antigen-specific cytotoxic T cell response. Taken together, this data show that CD40B cells home secondary lymphoid organs where they physically interact with T cells to induce antigen-specific T cell responses, thus underscoring their potential as cellular adjuvant for cancer immunotherapy.

Impaired T-Cell Function in B-Cell Lymphoma: A Direct Consequence of Events at the Immunological Synapse?

Tumors can escape immune destruction through the development of antigen loss variants and loss of antigen processing/presentation pathways, thereby rendering them invisible to T cells. Alternatively, mechanisms of peripheral T-cell tolerance that would normally be important for protection from the development of autoimmunity may also be co-opted to (i) generate an immuno-inhibitory tumor environment, (ii) promote development of regulatory cell populations, or (iii) cell-intrinsically inactivate tumor-specific T cells. Emerging evidence suggests that T-cell function is impaired in hematological malignancies, which may manifest from cognate interactions between T cells and the tumor. The immunological synapse forms the cognate T-cell and antigen-presenting cell interaction and is the site where key signalling events, including those delivered by co-inhibitory receptors, that determine the fate of T cells occur. Here, we review evidence that events at the immune synapse between T cells and malignant B cells and alterations in immune synapse function may contribute to loss of T-cell function in B-cell malignancies.

Group A Streptococcal vaccine candidate: contribution of epitope to size, antigen presenting cell interaction and immunogenicity.

Utilize lipopeptide vaccine delivery system to develop a vaccine candidate against Group A Streptococcus. Lipopeptides synthesized by solid-phase peptide synthesis-bearing carboxyl (C)-terminal and amino (N)-terminal Group A Streptococcus peptide epitopes. Nanoparticles formed were evaluated in vivo. Immune responses were induced in mice without additional adjuvant. We demonstrated for the first time that incorporation of the C-terminal epitope significantly enhanced the N-terminal epitope-specific antibody response and correlated with forming smaller nanoparticles. Antigen-presenting cells had increased uptake and maturation by smaller, more immunogenic nanoparticles. Antibodies raised by vaccination recognized isolates. Demonstrated the lipopeptidic nanoparticles to induce an immune response which can be influenced by the combined effect of epitope choice and size.

Abstract 44: Interleukin-27 Signaling is a Critical Regulator of Inflammation in Atherosclerosis

Atherosclerosis is chronic inflammatory disease, which affects blood vessels. While the pro-atherogenic role of various inflammatory cytokines was broadly investigated, less is known about contribution of anti-inflammatory cytokines with regard to their ability to control inflammation in vivo. Interleukin 27 (IL-27) was shown to play immunosuppressive function via multiple mechanisms. We tested whether IL-27 signaling is important to restrain inflammation in mouse models of atherosclerosis. We transplanted bone marrow from Il27ra -/- or Il27ra +/+ mice into atherosclerosis prone Ldlr -/- littermates. Recipients of Il27ra -/- marrow showed significantly larger atherosclerotic lesions in aortic roots, aortic arches and, most strikingly, in the abdominal aorta. Aortas contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. Concomitantly, the levels of IL-17A and IL-6 were significantly elevated in aortic tissue. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in aortas, atherosclerotic plaque growth and disease progression. Moreover, using our recently developed live imaging by two-photon microscopy, we found enhanced interaction between antigen presenting cells and T cells in the arterial wall of Il27ra deficient mice. Overall, IL-27 signaling in bone marrow-derived cells regulates atherosclerosis by controlling interaction of antigen presenting cells and T cells in the arterial wall and therefore curbing Th17 and Th1 lineage differentiation, TNF and IL-17 dependent chemokine expression and subsequent myeloid cell accumulation. Thus, our work establishes the importance of anti-inflammatory cytokine signaling in atherosclerosis and demonstrates novel anti-atherogenic role of IL-27.

Unconventional recognition of peptides by T cells and the implications for autoimmunity

The interaction of antigen-presenting cells with free peptides or a denatured protein can give rise to peptide-MHC class II complexes that are distinct from those generated after the processing of the whole protein. Such atypical peptide-MHC complexes can be recognized by unconventional 'type B' T cells that are not a component of the normal immune response to proteins. Importantly, these unconventional T cells can be found in the setting of autoimmunity. Here, we discuss unconventional peptide recognition by type B T cells and consider the implications for type 1 diabetes and other autoimmune diseases.