Capacity Of Antigen-presenting Cells Research Articles

Identification of Antigen Presenting Cell Subsets Supporting Human Tfh Differentiation.

CD4+ T follicular helper (Tfh) cells are essential for initiating and regulating efficient humoral responses in secondary lymphoid organs. Tfh polarization and differentiation is driven by multiple stimuli delivered by antigen presenting cells (APCs). APCs represent a complex population of immune cells, comprising several subpopulations (dendritic cells and macrophages) that are distinguished by their phenotype, ontogeny, and functions. In order to better identify and understand the role of the different APC subsets in human Tfh biology, we have used in vitro assays based on the co-culture of APCs and T cells. This chapter describes two complementary protocols. The first protocol describes an assay to study the capacity of APCs to drive Tfh polarization from naive CD4+ T cells. The second protocol is designed to address the role of APCs in modulating effector functions of mature Tfh cells.

A Multicompartment Mathematical Model Based on Host Immunity for Dissecting COVID-19 Heterogeneity

Background:As of early August 2021, more than 190 million people have developed coronavirus disease (COVID-19), a pandemic that has killed approximately 4 million people. Caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 exhibited a highly variable clinical course, ranging from a high proportion of asymptomatic and mild infections to severe and fatal disease. However, the immunological determinants underlying the heterogeneity of COVID-19 remain to be fully elucidated.Methods:To systemically analyze the immunopathogenesis of COVID-19, a multicompartment mathematical model based on both immunological principles and COVID-19-related work performed by the scientific community was built to illustrate the dynamics of host immunity after SARS-CoV-2 infection. We used ordinary differential equations (ODEs) to simulate the time-dependent functions of immunologic variations in the four compartments, which were draining lymph nodes, peripheral blood, lung and distant lymph nodes and spleen. Our model consisted of equations for 109 immunologic variations, which contained 223 parameters. K was used to characterize the adequacy of the SARS-CoV-2-specific naïve T/B cell pool; K I represented the hill coefficient of antigen-presenting cell (APC) differentiation. Further, we used method of pseudo landscape to visualize the effect of APC capacity and the SARS-CoV-2-specific naïve T/B cell pool on clinical outcomes.Results:Based on both immunologic knowledge and extensive COVID-19-related work performed by the scientific community, we constructed a knowledge-driven mathematical model that incorporated SARS-CoV-2 infection, bacterial infection, leukocyte chemotaxis, innate immunity and adaptive immunity. The model simulated and predicted the different trajectories of the viral load, bacterial load, immune cells, cytokines and infected epithelial cells in patients with different severities. A higher viral load and longer virus-shedding period were observed in patients with higher severity, along with an increase in SARS-CoV-2-infected lung epithelial cells. The trajectories of both peripheral blood IL-6 and lymphocytes predicted COVID-19 outcomes. Based on the distribution, trafficking and differentiation of immune cells after SARS-CoV-2 infection, we proposed that early-stage lymphopenia is related to lymphocyte chemotaxis. The delayed initiation of both innate and adaptive immunity resulted in elevated SARS-CoV-2 shedding and was a pivotal cause of COVID-19 severity. Spatiotemporally, viral shedding and postviral bacterial infection evoked stronger innate immunity. Viral shedding could be restrained by the rapid initiation of APC, antibody-secreting cell (ASC) and cytotoxic T cell (CTL). Moreover, our model predicted that the insufficient SARS-CoV-2-specific naïve T/B cell pools and inactive APC caused a series of chain reactions, including viral shedding, bacterial infection, sepsis and cytokine storms. Finally, pseudopotential analysis revealed that a high state characterized by severe bacterial infections and cytokine storms was a stable attractor for patients with insufficient SARS-CoV-2-specific naïve T/B cells and inactive APC (Figure 1).Conclusion:Overall, our analysis provided a comprehensive view of the dynamics of host immunity after SARS-CoV-2 infection and highlighted that the antigen-specific naïve T/B cell pool and APC ability may essentially determine COVID-19 heterogeneity from an immunological standpoint. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Helicobacter pylori infected gastric epithelial cells drive dendritic cells towards a tolerogenic phenotype.

Abstract The interactions of dendritic cells (DCs) with the gastric epithelium are thought to play a role in shaping DC function and thus the adaptive immune response to Helicobacter pylori (H. pylori) infection. We have shown that DCs are recruited to the H. pylori-infected gastric epithelium, positioning them for uptake of bacterial antigen from the gastric lumen. Using a gastric organoid model of H. pylori infection, we sought to define how the interactions between gastric epithelial cells and DCs regulate the antigen-presenting cell capacity of DCs. Supernatants were collected from organoids microinjected with H. pylori (infected) or PBS (mock), and monocyte-derived dendritic cells (MoDCs) were incubated with these supernatants. Flow cytometry data showed that the supernatant from infected organoids drove the DCs toward a tolerogenic state, as the expression of CD40, CD83, and CD86 was significantly decreased compared to incubation with supernatants from mock infected organoids, whereas CCR7 expression was increased consistent with a more tolerogenic phenotype. DCs treated with supernatants from infected, but not mock-infected organoids suppressed the proliferation of naïve autologous T cells. We also assessed T cell polarization using a cytokine array and found an increase in Th1, Th17 and Treg cytokines, but a decrease in Th2 cytokines in T cells that were challenged with DCs pre-treated with supernatants from infected organoids compared to mock-infected organoids. In summary, we have shown that H. pylori-infected gastric epithelium drives the DCs toward a tolerogenic state, resulting in reduced expression of maturation markers and CD4+ T cell proliferation while maintaining the DCs’ ability to induce T cell cytokine secretion.

Stanniocalcin 1 is a phagocytosis checkpoint driving tumor immune resistance.

Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss-of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an "eat-me" signal, and minimizes CRT membrane exposure, thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and Tcell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy.

Mucosal delivery of ESX-1–expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes

Tuberculosis (TB) claims 1.5 million lives per year. This situation is largely due to the low efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG) against pulmonary TB. The metabolic disease type 2 diabetes (T2D) is a risk factor for TB and the mechanisms underlying increased TB susceptibility in T2D are not well understood. Furthermore, it is unknown if new TB vaccines will provide protection in the context of T2D. Here we used a diet-induced murine model of T2D to investigate the underlying mechanisms of TB/T2D comorbidity and to evaluate the protective capacity of two experimental TB vaccines in comparison to conventional BCG. Our data reveal a distinct immune dysfunction that is associated with diminished recognition of mycobacterial antigens in T2D. More importantly, we provide compelling evidence that mucosal delivery of recombinant BCG strains expressing the Mycobacterium tuberculosis (Mtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 ∆92-95) are safe and confer superior immunity against aerosol Mtb infection in the context of T2D. Our findings suggest that the remarkable anti-TB immunity by these recombinant BCG strains is achieved via augmenting the numbers and functional capacity of antigen presenting cells in the lungs of diabetic mice.

Force-dependent trans-endocytosis by breast cancer cells depletes costimulatory receptor CD80 and attenuates T cell activation

In this study, we investigated the biophysical interaction between cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and CD80. CTLA-4 is a key molecule in immunosuppression, and CD80 is a costimulatory receptor promoting T cell activation. We observed that after cell-cell contact was established between breast cancer cells and antigen presenting cells (APCs), CTLA-4 expressed on the breast cancer cells bind to CD80 expressed on the APCs, and underwent trans-endocytosis to deplete CD80. Force measurement and live cell imaging revealed that upon binding to CD80, forces generated by breast cancer cells and transmitted via CTLA-4 were sufficiently strong to displace CD80 from the surface of APCs to be internalized by breast cancer cells. We further demonstrated that because of the force-dependent trans-endocytosis of CD80, the capacity of APCs to activate T cells was significantly attenuated. Furthermore, inhibiting force generation in cancer cells would increase the T cell activating capacity of APCs. Our results provide a possible mechanism behind the immunosuppression commonly seen in breast cancer patients, and may lead to a new strategy to restore anti-tumor immunity by inhibiting pathways of force-generation.

TLR2 and Dectin-1 Signaling in Mouse Hematopoietic Stem and Progenitor Cells Impacts the Ability of the Antigen Presenting Cells They Produce to Activate CD4 T Cells

Microbial recognition by pattern recognition receptors (PRRs) expressed on hematopoietic stem and progenitor cells (HSPCs) not only activates myelopoiesis but also programs the function of the monocytes and macrophages they produce. For instance, changes in HSPC programming modify the ability of macrophages derived from them to produce inflammatory cytokines. While HSPCs exposed to a TLR2 agonist give rise to tolerized macrophages (lower proinflammatory cytokine production), HSPCs treated with Dectin-1 ligands produce trained macrophages (higher proinflammatory cytokine production). However, nothing is known about the impact of HSPC exposure to microbes on the function of antigen presenting cells (APCs). In this study we evaluated whether treatment of murine bone marrow HSPCs with a TLR2 or Dectin-1 ligand impacts the antigen presenting capacity of APCs derived from them in vitro. Following activation with microbial ligands or Candida albicans yeasts, APCs derived from TLR2/Dectin-1-programed HSPCs exhibit altered expression of MHCII (signal 1), co-stimulatory molecules (CD40, CD80 and CD86; signal 2) and cytokines (TNF-α, IL-6, IL-12 p40 and IL-2; signal 3). Moreover, APCs derived from TLR2/Dectin-1-programed HSPCs prime enhanced Th1 and Th17 responses, which are important for antifungal defense, in CD4 T cell cocultures. Overall, these results demonstrate for the first time that microbial detection by bone marrow HSPCs can modulate the adaptive immune response by inducing the production of APCs with an altered phenotype.

Pancreatic β-cells express major histocompatibility complex classII: Do diabetic β-cells have the capacity of antigen-presenting cells?

Russell etal. showed that major histocompatibility complex classII is expressed in pancreatic β-cells by a highly accurate method called transcriptome analysis. Pancreatic β-cells might have the capacity as antigen-presenting cells.

Skin-restricted commensal colonization accelerates skin graft rejection.

Solid organ transplantation can treat end-stage organ failure, but the half-life of transplanted organs colonized with commensals is much shorter than that of sterile organs. Whether organ colonization plays a role in this shorter half-life is not known. We have previously shown that an intact whole-body microbiota can accelerate the kinetics of solid organ allograft rejection in untreated colonized mice when compared to germ-free (GF) or to antibiotic-pre-treated colonized mice, by enhancing the capacity of antigen presenting cells (APCs) to activate graft-reactive T cells. However, the contribution of intestinal versus skin microbiota to these effects was unknown. Here, we demonstrate that colonizing the skin of GF mice with a single commensal, Staphylococcus epidermidis (S. epi), while preventing intestinal colonization with oral vancomycin, was sufficient to accelerate skin graft rejection. Notably, unlike the mechanism by which whole-body microbiota accelerates skin graft rejection, cutaneous S. epi did not enhance the priming of alloreactive T cells in the skin-draining lymph nodes (LNs). Rather, cutaneous S. epi augmented the ability of skin APCs to drive the differentiation of alloreactive T cells. This study reveals that the extra-intestinal donor microbiota can affect transplant outcome and may contribute to the shorter half-life of colonized organs.

H1-Antihistamines for Allergic Diseases: Old Aged but Not Old-Fashioned Drugs

Histamine is a chemical messenger synthesized from the amino acid histidine by L-histidine decarboxylase. It plays an important role in the system of immunoregulation and in acute and chronic allergic inflammation binding to four subtypes of receptors H1, H2, H3 and H4, described as heptahelical transmembrane molecules that activate specific G-proteins. These receptors placed on the membranes of different cellular jambs (mast cells, endothelial cells, sensory nerve fibres, bronchial smooth muscle) cause different biological actions: Vasodilatation, increased vascular permeability, itching, smooth muscle contraction, coronary spasm, sleep-wake rhythm regulation. Histamine interaction with H1-receptors potentially leads to increasing antigen-presenting cell capacity, release of histamine and other mediators from mast cells and basophils inducing cellular adhesion molecule expression and chemotaxis of eosinophils and neutrophils.

Hyperlipidemia and Allograft Rejection.

Advances in the development of immunosuppressive drug regimens have led to impressive survival rates in the year following organ transplantation. However rates of long-term graft dysfunction remain undesirably high. Recently it has been shown that co-morbidities in the patient population may affect graft survival. In mouse models, hyperlipidemia, a co-morbidity present in the majority of cardiac transplant patients, can significantly alter T cell responses to cardiac and skin allografts, and accelerate graft rejection. Here we review recent advances in our understanding of how alterations in lipids affect immune function and graft survival. Recent work in humans has highlighted the importance of controlling low density lipoprotein (LDL) levels in transplant recipients to reduce the development of chronic allograft vasculopathy (CAV). High serum levels of cholesterol containing particles leads to extensive immune system changes to T cell proliferation, differentiation and suppression. Changes in B cell subsets, and the ability of antigen presenting cells to stimulate T cells in hyperlipidemic animals may also contribute to increased organ allograft rejection. Cholesterol metabolism is a critical cellular pathway for proper control of immune cell homeostasis and activation. Increasing evidence in both human, and in mouse models shows that elevated levels of serum cholesterol can have profound impact on the immune system. Hyperlipidemia has been shown to increase T cell activation, alter the development of T helper subsets, increase the inflammatory capacity of antigen presenting cells (APC) and significantly accelerate graft rejection in several models.

Treatment Combining CD200 Immune Checkpoint Inhibitor and Tumor-Lysate Vaccination after Surgery for Pet Dogs with High-Grade Glioma.

Recent advances in immunotherapy have included inhibition of immune checkpoint proteins in the tumor microenvironment and tumor lysate-based vaccination strategies. We combined these approaches in pet dogs with high-grade glioma. Administration of a synthetic peptide targeting the immune checkpoint protein, CD200, enhanced the capacity of antigen-presenting cells to prime T-cells to mediate an anti-glioma response. We found that in canine spontaneous gliomas, local injection of a canine-specific, CD200-directed peptide before subcutaneous delivery of an autologous tumor lysate vaccine prolonged survival relative to a historical control treated with autologous tumor lysate alone (median survivals of 12.7 months and 6.36 months, respectively). Antigen-presenting cells and T-lymphocytes primed with this peptide suppressed their expression of the inhibitory CD200 receptor, thereby enhancing their ability to initiate immune reactions in a glioblastoma microenvironment replete with the immunosuppressive CD200 protein. These results support consideration of a CD200 ligand as a novel glioblastoma immunotherapeutic agent.

Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease

The anti-CD20 antibody ocrelizumab, approved for treatment of multiple sclerosis, leads to rapid elimination of B cells from the blood. The extent of B cell depletion and kinetics of their recovery in different immune compartments is largely unknown. Here, we studied how anti-CD20 treatment influences B cells in bone marrow, blood, lymph nodes, and spleen in models of experimental autoimmune encephalomyelitis (EAE). Anti-CD20 reduced mature B cells in all compartments examined, although a subpopulation of antigen-experienced B cells persisted in splenic follicles. Upon treatment cessation, CD20+ B cells simultaneously repopulated in bone marrow and spleen before their reappearance in blood. In EAE induced by native myelin oligodendrocyte glycoprotein (MOG), a model in which B cells are activated, B cell recovery was characterized by expansion of mature, differentiated cells containing a high frequency of myelin-reactive B cells with restricted B cell receptor gene diversity. Those B cells served as efficient antigen-presenting cells (APCs) for activation of myelin-specific T cells. In MOG peptide-induced EAE, a purely T cell-mediated model that does not require B cells, in contrast, reconstituting B cells exhibited a naive phenotype without efficient APC capacity. Our results demonstrate that distinct subpopulations of B cells differ in their sensitivity to anti-CD20 treatment and suggest that differentiated B cells persisting in secondary lymphoid organs contribute to the recovering B cell pool.

Properly folded and functional PorB from Neisseria gonorrhoeae inhibits dendritic cell stimulation of CD4+ T cell proliferation

Neisseria gonorrhoeae is an exclusive human pathogen that evades the host immune system through multiple mechanisms. We have shown that N. gonorrhoeae suppresses the capacity of antigen-presenting cells to induce CD4+ T cell proliferation. In this study, we sought to determine the gonococcal factors involved in this adaptive immune suppression. We show that suppression of the capacity of antigen-pulsed dendritic cells to induce T cell proliferation is recapitulated by administration of a high-molecular-weight fraction of conditioned medium from N. gonorrhoeae cultures, which includes outer membrane vesicles that are shed during growth of the bacteria. N. gonorrhoeae PorB is the most abundant protein in N. gonorrhoeae-derived vesicles, and treatment of dendritic cells with purified recombinant PorB inhibited the capacity of the cells to stimulate T cell proliferation. This immunosuppressive feature of purified PorB depended on proper folding of the protein. PorB from N. gonorrhoeae, as well as other Neisseria species and other Gram-negative bacterial species, are known to activate host Toll-like receptor 2 (TLR2) signaling. Published studies have demonstrated that purified Neisseria PorB forms proteinacious nanoparticles, termed proteosomes, when detergent micelles are removed. Unlike folded, detergent-solubilized PorB, PorB proteosomes stimulate immune responses. We now demonstrate that the formation of PorB proteosomes from structurally intact PorB eliminates the immunosuppressive property of the protein while enhancing TLR2 stimulation. These findings suggest that gonococcal PorB present in shed outer membrane vesicles plays a role in suppression of adaptive immune responses to this immune-evasive pathogen.

Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma.

Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells (APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma (HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from non-cancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.

Comprehensive Analysis of the Activation and Proliferation Kinetics and Effector Functions of Human Lymphocytes, and Antigen Presentation Capacity of Antigen-Presenting Cells in Xenogeneic Graft-Versus-Host Disease

Xenogeneic graft-versus-host disease (GVHD) models in highly immunodeficient mice are currently being used worldwide to investigate human immune responses against foreign antigens in vivo. However, the individual roles of CD4+ and CD8+ T cells, and donor/host hematopoietic and nonhematopoietic antigen-presenting cells (APCs) in the induction and development of GVHD have not been fully investigated. In the present study, we comprehensively investigated the immune responses of human T cells and the antigen presentation capacity of donor/host hematopoietic and nonhematopoietic APCs in xenogeneic GVHD models using nonobese diabetic/Shi-scid-IL2rgnull mice. CD4+ T cells and, to a lesser extent, CD8+ T cells individually mediated potentially lethal GVHD. In addition to inflammatory cytokine production, CD4+ T cells also supported the activation and proliferation of CD8+ T cells. Using bone marrow chimeras, we demonstrated that host hematopoietic, but not nonhematopoietic, APCs play a critical role in the development of CD4+ T cell-mediated GVHD. During early GVHD, we detected 2 distinct populations in memory CD4+ T cells. One population was highly activated and proliferated in major histocompatibility complex antigen (MHC)+/+ mice but not in MHC−/− mice, indicating alloreactive T cells. The other population showed a less activated and slowly proliferative status regardless of host MHC expression, and was associated with higher susceptibility to apoptosis, indicating nonalloreactive T cells in homeostasis-driven proliferation. These observations are clinically relevant to donor T cell response after allogeneic hematopoietic stem cell transplantation. Our findings provide a better understanding of the immunobiology of humanized mice and support the development of novel options for the prevention and treatment for GVHD.

Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response.

Inflammation is typically induced in response to a microbial infection. The release of proinflammatory cytokines enhances the stimulatory capacity of antigen-presenting cells, as well as recruits adaptive and innate immune effectors to the site of infection. Once the microbe is cleared, inflammation is resolved by various mechanisms to avoid unnecessary tissue damage. Autoimmunity arises when aberrant immune responses target self-tissues causing inflammation. In type 1 diabetes (T1D), T cells attack the insulin producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by in part altering central and peripheral tolerance inducing events. This results in the development and expansion of β cell-specific effector T cells (Teff) which mediate islet inflammation. Unlike protective immunity where inflammation is terminated, autoimmunity is sustained by chronic inflammation. In this review, we will highlight the key events which initiate and sustain T cell-driven pancreatic islet inflammation in nonobese diabetic mice and in human T1D. Specifically, we will discuss: (i) dysregulation of thymic selection events, (ii) the role of intrinsic and extrinsic factors that enhance the expansion and pathogenicity of Teff, (iii) defects which impair homeostasis and suppressor activity of FoxP3-expressing regulatory T cells, and (iv) properties of β cells which contribute to islet inflammation.

Vaccine adjuvant MF59 promotes the intranodal differentiation of antigen-loaded and activated monocyte-derived dendritic cells.

MF59 is an oil-in-water emulsion adjuvant approved for human influenza vaccination in European Union. The mode of action of MF59 is not fully elucidated yet, but results from several years of investigation indicate that MF59 establishes an immunocompetent environment at injection site which promotes recruitment of immune cells, including antigen presenting cells (APCs), that are facilitated to engulf antigen and transport it to draining lymph node (dLN) where the antigen is accumulated. In vitro studies showed that MF59 promotes the differentiation of monocytes to dendritic cells (Mo-DCs). Since after immunization with MF59, monocytes are rapidly recruited both at the injection site and in dLN and appear to have a morphological change toward a DC-like phenotype, we asked whether MF59 could play a role in inducing differentiation of Mo-DC in vivo. To address this question we immunized mice with the auto-fluorescent protein Phycoerythrin (PE) as model antigen, in presence or absence of MF59. We measured the APC phenotype and their antigen uptake within dLNs, the antigen distribution within the dLN compartments and the humoral response to PE. In addition, using Ovalbumin as model antigen, we measured the capacity of dLN APCs to induce antigen-specific CD4 T cell proliferation. Here, we show, for the first time, that MF59 promotes differentiation of Mo-DCs within dLNs from intranodal recruited monocytes and we suggest that this differentiation could take place in the medullary compartment of the LN. In addition we show that the Mo-DC subset represents the major source of antigen-loaded and activated APCs within the dLN when immunizing with MF59. Interestingly, this finding correlates with the enhanced triggering of antigen-specific CD4 T cell response induced by LN APCs. This study therefore demonstrates that MF59 is able to promote an immunocompetent environment also directly within the dLN, offering a novel insight on the mechanism of action of vaccine adjuvants based on emulsions.

Activation status of mucosal-associated invariant T cells reflects disease activity and pathology of systemic lupus erythematosus

BackgroundMucosal-associated invariant T (MAIT) cells are innate-like lymphocytes constituting a large proportion of peripheral blood T cells expressing αβ T-cell receptor in humans. In this study, we aimed to investigate their involvement in systemic lupus erythematosus (SLE).MethodsPeripheral blood MAIT cells from patients with SLE were assessed for their frequency, activation markers, and cell death by flow cytometry. The correlation between plasma cytokine levels and CD69 expression on MAIT cells was analyzed. The major histocompatibility complex class I-related protein MR1-restricted antigen-presenting capacity of antigen-presenting cells was investigated. Cytokine-mediated activation of MAIT cells in the absence of exogenous antigens was also examined.ResultsThe frequency of MAIT cells was markedly reduced in SLE. The reduced number of MAIT cells was not attributable to the downregulation of surface markers, but it was partially due to the enhanced cell death of MAIT cells, possibly by activation-induced cell death. The CD69 expression levels on MAIT cells in SLE correlated with disease activity. Moreover, monocytes from patients with SLE exhibited increased ability to induce MAIT cell activation. The plasma concentration of interleukin (IL)-6, IL-18, and interferon (IFN)-α positively correlated with the expression levels of CD69 on MAIT cells in SLE. MAIT cells were activated by cytokines, including IFN-α, IL-15, and IL-12 plus IL-18, in the absence of exogenous antigens.ConclusionsThese results suggest that MAIT cells reflect the pathological condition of SLE and that their activated status correlates with presence of disease.

Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients

ABSTRACTNew treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6–9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy.