Despite effective anti-viral therapies, cytomegalovirus (CMV) is still associated with direct (CMV disease) and indirect effects (rejection and poor graft survival) in kidney transplant recipients. Recently, an unconventional T cell population (collectively designated as Vδ2neg γδ T cells) has been characterized during the anti-CMV immune response in all solid-organ and bone-marrow transplant recipients, neonates, and healthy people. These CMV-induced Vδ2neg γδ T cells undergo a dramatic and stable expansion after CMV infection, in a conventional “adaptive” manner. Similarly, as CMV-specific CD8+ αβ T cells, they exhibit an effector/memory TEMRA phenotype and cytotoxic effector functions. Activation of Vδ2neg γδ T cells by CMV-infected cells involves the γδ T cell receptor (TCR) and still ill-defined co-stimulatory molecules such as LFA-1. A multiple of Vδ2neg γδ TCR ligands are apparently recognized on CMV-infected cells, the first one identified being the major histocompatibility complex-related molecule endothelial protein C receptor. A singularity of CMV-induced Vδ2neg γδ T cells is to acquire CD16 expression and to exert an antibody-dependent cell-mediated inhibition on CMV replication, which is controlled by a specific cytokine microenvironment. Beyond the well-demonstrated direct anti-CMV effect of Vδ2neg γδ T cells, unexpected indirect effects of these cells have been also observed in the context of kidney transplantation. CMV-induced Vδ2neg γδ T cells have been involved in surveillance of malignancy subsequent to long-term immunosuppression. Moreover, CMV-induced CD16+ γδ T cells are cell effectors of antibody-mediated rejection of kidney transplants, and represent a new physiopathological contribution to the well-known association between CMV infection and poor graft survival. All these basic and clinical studies paved the road to the development of a future γδ T cell-based immunotherapy. In the meantime, γδ T cell monitoring should prove a valuable immunological biomarker in the management of CMV infection.
antibody-mediated rejection; cancer; cytomegalovirus; gamma-delta T cells; lymphocytes; renal transplantation
Intravenous immunoglobulin (IVIG) is used as replacement therapy in patients with antibody deficiencies and at higher dosages in immune-mediated disorders. Although different mechanisms have been described in vitro, the in vivo immunomodulatory effects of IVIG are poorly understood. Different studies have suggested that IVIG modulates B-cell functions as activation, proliferation, and apoptosis. Recently, it was shown that IVIG induces in vitro B-cell unresponsiveness similar to anergy. In accord with this, we recently reported that IVIG therapy in patients affected by common variable immunodeficiency (CVID) interferes in vivo with the B-cell receptor (BCR) signaling by increasing constitutive ERK activation and by reducing the phosphorylated ERK increment induced by BCR cross-linking. Moreover, we observed that IVIG induces in CVID patients an increase of circulating CD21low B-cells, an unusual population of anergic-like B-cells prone to apoptosis. Therefore, IVIG at replacement dose in vivo could prime B-cells to an anergic, apoptotic program. Here, we discuss these recent findings, which may improve our understanding of the immunomodulatory effects of IVIG, individualizing single involved molecules for more specific treatments.
intravenous immunoglobulin; B lymphocytes; immunomodulation; CD21low B-cell; autoimmune disease
The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation, and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The “Warburg effect” originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here, we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1α. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases.
glucose transporter 1; PI3K; metabolism; mTOR; HIF-1α; immune activation; HIV; inflammation
Antimicrobial peptides (AMPs) represent a group of small (6–100 amino acids), biologically active molecules, which are produced by plants, mammals, and microorganisms (1). An important element of the innate immune response, AMP, possesses potent antibiotic, antifungal, and antiviral activities. Furthermore, AMP may be involved in a number of other processes such as angiogenesis and modulation of the immune response such as stimulation of chemokines and chemotaxis of leukocytes. AMPs have been proposed as alternative therapies for infectious diseases. AMP may also exert cytotoxic activity against tumor cells. Further understanding of the biological function of these peptides during tumor development and progression may aid in the development of novel anti-tumor therapies with refined application of innate molecules. AMP and complement have distinct roles to play in shaping the microenvironment (Table 1). Components of the complement system are integral contributors in responding to infection and sterile inflammation. Moreover, complement plays a role in the trafficking of cells in the tumor microenvironment, and thereby possibly in the immune response to cancer. This article will try to outline characteristics of AMP and complement in mobilization and recruitment of cells in tumor microenvironment.
defensins; cathelicidins; anti-tumor activity; c5a; cell recruitment and activation
reproductive immunology; immunology; obstetrics; hematology; endocrinology
plasma cell; B-cell; cell cycle; IL21; autophagy; B1; autoimmunity; myeloma
The contributions of γδ T-cells to immunity to infection or tumors critically depend on their activation and differentiation into effectors capable of secreting cytokines and killing infected or transformed cells. These processes are molecularly controlled by surface receptors that capture key extracellular cues and convey downstream intracellular signals that regulate γδ T-cell physiology. The understanding of how environmental signals are integrated by γδ T-cells is critical for their manipulation in clinical settings. Here, we discuss how different classes of surface receptors impact on human and murine γδ T-cell differentiation, activation, and expansion. In particular, we review the role of five receptor types: the T-cell receptor (TCR), costimulatory receptors, cytokine receptors, NK receptors, and inhibitory receptors. Some of the key players are the costimulatory receptors CD27 and CD28, which differentially impact on pro-inflammatory subsets of γδ T-cells; the cytokine receptors IL-2R, IL-7R, and IL-15R, which drive functional differentiation and expansion of γδ T-cells; the NK receptor NKG2D and its contribution to γδ T-cell cytotoxicity; and the inhibitory receptors PD-1 and BTLA that control γδ T-cell homeostasis. We discuss these and other receptors in the context of a five-step model of receptor signaling in γδ T-cell differentiation and activation, and discuss its implications for the manipulation of γδ T-cells in immunotherapy.
γδ T-cells; T-cell receptor; T-cell costimulation; cytokines; natural killer receptors
Hematopoietic stem-cell transplantation (HSCT) is the most potent curative therapy for many malignant and non-malignant disorders. Unfortunately, a major complication of HSCT is graft-versus-host disease (GVHD), which is mediated by tissue damage resulting from the conditioning regimens before the transplantation and the alloreaction of dual immune components (activated donor T-cells and recipient’s antigen-presenting cells). This tissue damage leads to the release of alarmins and the triggering of pathogen-recognition receptors that activate the innate immune system and subsequently the adaptive immune system. Alarmins, which are of endogenous origin, together with the exogenous pathogen-associated molecular patterns (PAMPs) elicit similar responses of danger signals and represent the group of damage-associated molecular patterns (DAMPs). Effector cells of innate and adaptive immunity that are activated by PAMPs or alarmins can secrete other alarmins and amplify the immune responses. These complex interactions and loops between alarmins and PAMPs are particularly potent at inducing and then aggravating the GVHD reaction. In this review, we highlight the role of these tissue damaging molecules and their signaling pathways. Interestingly, some DAMPs and PAMPs are organ specific and GVHD-induced and have been shown to be interesting biomarkers. Some of these molecules may represent potential targets for novel therapeutic approaches.
graft-versus-host disease; danger signals; tissue damage; alarmins; pathogen-associated molecular patterns; damage-associated molecular patterns; innate immunity; biomarkers
Vaccine-based cancer immunotherapy has generated highly variable clinical results due to differing methods of vaccine preparation and variation in patient populations among other lesser factors. Moreover, these clinical responses do not necessarily correspond with the induction of tumor-specific cytotoxic lymphocytes. Here, we review the participation of natural killer (NK) cells as alternative immune components that could cooperate in successful vaccination treatment. NK cells have been described as helper cells in dendritic cell-based cancer vaccines, but the role in other kinds of vaccination strategies (whole cells, peptide, or DNA-based vaccines) is poorly understood. In this article, we address the following issues regarding the role of NK cells in cancer vaccines: NK cell anti-tumor action sites, and the loci of NK cell interaction with other immune cells; descriptions of new data on the memory characteristics of NK cells described in infectious diseases; and finally phenotypical and functional changes after vaccination measured by immunomonitoring in preclinical and clinical settings.
cancer vaccines; natural killer cells; immunomonitoring; dendritic cells vaccines; NK cells–dendritic cells crosstalk
Immune cells play an integral role in affecting successful reproductive function. Indeed, disturbed or aberrant immune function has been identified as primary mechanisms behind infertility. In contrast to the extensive body of literature that exists for human and mouse, studies detailing the immunological interaction between the embryo and the maternal endometrium are quite few in cattle. Nevertheless, by reviewing the existing studies and extrapolating from sheep, pig, mouse, and human data, we can draw a reasonably comprehensive picture. Key contributions of immune cell populations include granulocyte involvement in follicle differentiation and gamete transfer, monocyte invasion of the peri-ovulatory follicle and their subsequent role in corpus luteum formation and the pivotal roles of maternal macrophage and dendritic cells in key steps of the establishment of pregnancy, particularly, the maternal immune response to the embryo. These contributions are reviewed in detail below and key findings are discussed.
cow; fertility; macrophage; cytokine; immune function
Schistosomiasis is a debilitating disease that represents a major health problem in at least 74 tropical and subtropical countries. Current disease control strategies consist mainly of chemotherapy, which cannot prevent recurrent re-infection of people living in endemic area. In the last decades, many researchers made a remarkable effort in the search for an effective vaccine to provide long-term protection. Parasitic platyhelminthes of Schistosoma genus, which cause the disease, live in the blood vessels of definitive hosts where they are bathed in host blood for many years. Among the most promising molecules as vaccine candidates are the proteins present in the host–parasite interface, so numerous tegument antigens have been assessed and the achieved protection never got even close to 100%. Besides the tegument, the digestive tract is the other major site of host–parasite interface. Since parasites feed on blood, they need to swallow a considerable amount of blood for nutrient acquisition. Host blood ingested by schistosomes passes through the esophagus and reaches the gut where many peptidases catalyze the proteolysis of blood cells. Recent studies show the emergence of antigens related to the parasite blood feeding, such as esophageal gland proteins, proteases, and other proteins related to nutrient uptake. Herein, we review what is known about Schistosoma mansoni digestive tract proteins, emphasizing the ones described as potential vaccine candidates.
Schistosoma mansoni; vaccine; digestive tract; esophageal gland; gastrodermis; proteases
type I interferons; vaccine adjuvant; viral; bacterial
cell culture platform; extracellular vesicle; cell therapy; exosomes; GMP conditions; EV quality service
TCR; immunodeficiency; diagnosis; γδ; T lymphocyte
miR-21 is one of the most highly expressed members of the small non-coding microRNA family in many mammalian cell types. Its expression is further enhanced in many diseased states including solid tumors, cardiac injury, and inflamed tissue. While the induction of miR-21 by inflammatory stimuli cells has been well documented in both hematopoietic cells of the immune system (particularly monocytes/macrophages but also dendritic and T-cells) and non-hematopoietic tumorigenic cells, the exact functional outcome of this elevated miR-21 is less obvious. Recent studies have confirmed a key role for miR-21 in the resolution of inflammation and in negatively regulating the pro-inflammatory response induced by many of the same stimuli that trigger miR-21 induction itself. In particular, miR-21 has emerged as a key mediator of the anti-inflammatory response in macrophages. This suggests that miR-21 inhibition in leukocytes will promote inflammation and may enhance current therapies for defective immune responses such as cancer, mycobacterial vaccines, or Th2-associated allergic inflammation. At the same time, miR-21 has been shown to promote inflammatory mediators in non-hematopoietic cells resulting in neoplastic transformation. This review will focus on functional studies of miR-21 during inflammation, which is complicated by the numerous molecular targets and processes that have emerged as miR-21 sensitive. It may be that the exact functional outcome of miR-21 is determined by multiple features including the cell type affected, the inducing signal, the transcriptomic profile of the cell, which ultimately affect the availability and ability to engage different target mRNAs and bring about its unique responses. Reviewing this data may illustrate that RNA-based oligonucleotide therapies for different diseases based upon miR-21 may have to target the unique and operative miRNA:mRNA interactions’ functionally active in disease.
miR-21; inflammation; cancer; PDCD4; macrophage
Most cells physiologically release vesicles as way of intercellular communication. The so-called Extracellular Vesicles (EVs) include exosomes, ectosomes, and apoptotic bodies, which basically differ in their composition and subcellular origin. Specifically, EVs found in urine reflect the state of the urinary system, from podocytes to renal-tubular cells, thus making them an excellent source of samples for the study of kidney physiology and pathology. Several groups have focused on defining biomarkers of kidney-related disorders, from graft rejection to metabolic syndromes. So far, the lack of a standard protocol for EVs isolation precludes the possibility of a proper comparison among the different biomarkers proposed in the literature, stressing the need for validation of these biomarkers not only in larger cohorts of patients but also considering the different methods for EVs isolation. In this review, we aim to gather the current knowledge about EVs-related biomarkers in kidney diseases, with a special emphasis in the methods used to date for EVs enrichment, and discussing the need for more specific protocols of EV isolation in clinical practice.
urinary extracellular vesicles; kidney disease; biomarker; therapy; isolation
The 1990s brought a burst of information regarding the structure, expression pattern, and role in leukocyte migration and adhesion of chemokines and their receptors. At that time, the FDA approved the first therapeutic antibodies for cancer treatment. A few years later, it was reported that the chemokine receptors CXCR4 and CCR7 were involved on directing metastases to liver, lung, bone marrow, or lymph nodes, and the over-expression of CCR4, CCR6, and CCR9 by certain tumors. The possibility of inhibiting the interaction of chemokine receptors present on the surface of tumor cells with their ligands emerged as a new therapeutic approach. Therefore, many research groups and companies began to develop small molecule antagonists and specific antibodies, aiming to neutralize signaling from these receptors. Despite great expectations, so far, only one anti-chemokine receptor antibody has been approved for its clinical use, mogamulizumab, an anti-CCR4 antibody, granted in Japan to treat refractory adult T-cell leukemia and lymphoma. Here, we review the main achievements obtained with anti-chemokine receptor antibodies for cancer immunotherapy, including discovery and clinical studies, proposed mechanisms of action, and therapeutic applications.
chemokine receptors; therapeutic antibodies; clinical trials; immunotherapy; cancer
It is well understood that multiple antimicrobial peptides (AMPs) are constitutively deployed by the epithelium to bolster the innate defenses along the entire length of the intestines. In addition to this constitutive/homeostatic production, AMPs may be inducible and levels changed during disease. In contrast to this level of knowledge on AMP sources and roles in the intestines, our understanding of the complement cascade in the healthy and diseased intestines is rudimentary. Epithelial cells make many complement proteins and there is compelling evidence that complement becomes activated in the lumen. With the common goal of defending the host against microbes, the opportunities for cross-talk between these two processes is great, both in terms of actions on the target microbes but also on regulating the synthesis and secretion of the alternate family of molecules. This possibility is beginning to become apparent with the finding that colonic epithelial cells possess anaphylatoxin receptors. There still remains much to be learned about the possible points of collaboration between AMPs and complement, for example, whether there is reciprocal control over expression in the intestinal mucosa in homeostasis and restoring the balance following infection and inflammation.
antimicrobial peptide; defensin; cathelicidin; Paneth cell; anaphylatoxin; lectin pathway; intestine; colitis
Tryptophan is required for T lymphocyte effector functions. Its degradation is one of the mechanisms selected by tumors to resist immune destruction. Two enzymes, tryptophan-2,3-dioxygenase and indoleamine 2,3-dioxygenase 1, control tryptophan degradation through the kynurenine pathway. A third protein, indoleamine 2,3-dioxygenase 2, was identified more recently. All three enzymes were reported to be expressed in tumors, and are candidate targets for pharmacological inhibition aimed at restoring effective anti-tumoral immunity. In this review, we compare these three enzymes in terms of structure, activity, regulation, and expression in healthy and cancerous tissues, in order to appreciate their relevance to tumoral immune resistance.
indoleamine 2,3-dioxygenase; tryptophan-2,3-dioxygenase; dendritic cells; tumor; immunosuppression; tryptophan; adaptive resistance
The IgE response has been associated with both allergic reactions and immunity to metazoan parasites. Recently, we hypothesized that all environmental allergens bear structural homology to IgE-binding antigens from metazoan parasites and that this homology defines the relatively small number of protein families containing allergenic targets. In this study, known allergen structures (Pfam domains) from major environmental allergen families were used to predict allergen-like (SmProfilin, SmVAL-6, SmLipocalin, SmHSP20, Sm triosephosphate isomerase, SmThioredoxin, Sm superoxide dismutase, SmCyclophilin, and Sm phosphoglycerate kinase) and non-allergen-like [Sm dynein light chain (SmDLC), SmAldolase SmAK, SmUbiquitin, and Sm14-3-3] proteins in Schistosoma mansoni. Recombinant antigens were produced in Escherichia coli and IgG1, IgG4, and IgE responses against them measured in a cohort of people (n = 222) infected with S. mansoni. All allergen-like antigens were targeted by IgE responses in infected subjects, whilst IgE responses to the non-allergen-like antigens, SmAK, SmUbiquitin, and Sm14-3-3 were essentially absent being of both low prevalence and magnitude. Two new IgE-binding Pfam domain families, not previously described in allergen family databases, were also found, with prevalent IgE responses against SmDLC (PF01221) and SmAldolase (PF00274). Finally, it was demonstrated that immunoregulatory serological processes typically associated with allergens also occurred in responses to allergen-like proteins in S. mansoni infections, including the production of IgG4 in people responding with IgE and the down-regulation of IgE in response to increased antigen exposure from S. mansoni eggs. This study establishes that structures of known allergens can be used to predict IgE responses against homologous parasite allergen-like molecules (parallergens) and that serological responses with IgE/IgG4 to parallergens mirror those seen against allergens, supporting our hypothesis that allergenicity is rooted in expression of certain protein domain families in metazoan parasites.
schistosomiasis mansoni; allergenicity; IgE; IgG4; parasite allergens; metazoan parasite; helminth proteins
Considering that the non-classical HLA-G molecule has well-recognized tolerogenic properties, HLA-G expression is expected to be deleterious when present in tumor cells and in cells chronically infected by viruses, whereas HLA-G expression is expected to be advantageous in autoimmune disorders. The expression of HLA-G on tissue or peripheral blood cells, the levels of soluble HLA-G and polymorphic sites along the gene have been studied in several disorders. In this study, we revised the role of the molecule and polymorphic sites along the HLA-G gene in tumors, viral hepatitis, and parasitic disorders. Overall, several lines of evidence clearly show that the induction of HLA-G expression in tumors has been associated with worse disease outcome and disease spread. In addition, the few studies conducted on hepatitis and parasitic disorders indicate that HLA-G may contribute to disease pathogenesis. Few isolated polymorphic sites, primarily located at the coding or 3′ untranslated HLA-G region, have been evaluated in these disorders, and a complete HLA-G typing together with the study of gene regulatory elements may further help on the understanding of the influence of the genetic background on disease susceptibility.
HLA-G; tumors; viral hepatitis; parasitic disorders; polymorphism
Sugar molecules play a vital role on both microbial and mammalian cells, where they are involved in cellular communication, govern microbial virulence, and modulate host immunity and inflammatory responses. The complement cascade, as part of a host’s innate immune system, is a potent weapon against invading bacteria but has to be tightly regulated to prevent inappropriate attack and damage to host tissues. A number of complement regulators, such as factor H and properdin, interact with sugar molecules, such as glycosaminoglycans (GAGs) and sialic acid, on host and pathogen membranes and direct the appropriate complement response by either promoting the binding of complement activators or inhibitors. The binding of these complement regulators to sugar molecules can vary from location to location, due to their different specificities and because distinct structural and functional subpopulations of sugars are found in different human organs, such as the brain, kidney, and eye. This review will cover recent studies that have provided important new insights into the role of GAGs and sialic acid in complement regulation and how sugar recognition may be compromised in disease.
sialic acid; heparan sulfate; glycosaminoglycan; complement factor H; properdin; innate immunity; tissue specificity; complement regulation
inflammatory bowel diseases; inflammation; innate lymphocytes; MAIT cells; cytokines
Properdin is a normal serum protein that increases the production of complement activation products by binding C3b integral to convertase complexes and amplifying their activity at the site of activation. Thereby, it not only can aid in the resolution of infection but also contribute to tissue damage. In human sepsis, circulating complement C3 concentrations are decreased, though C3 is described as a positive acute phase reactant. However, properdin levels in human sepsis have not been reported. In this study, serum from 81 critically ill patients (predominately abdominal and respiratory sepsis) were analyzed for properdin levels at defined points of their stay in the intensive care unit (ICU) and compared with 61 age and sex-matched healthy volunteers. Properdin concentrations were significantly decreased in patients with sepsis on admission to ICU, but increased after clinical recovery to exceed levels observed in healthy volunteers. Properdin concentrations at ICU admission were decreased in non-survivors of sepsis compared to survivors, but this did not correlate with APACHE II score. However, pathologically low properdin levels (<7 μg/ml) were related to increased duration of treatment.
sepsis; complement; properdin; intensive care; recovery
Natural killer (NK) cells are a key constituent of the innate immune system, protecting against bacteria, virally infected cells, and cancer. Recognition and protective function against such cells are dictated by activating and inhibitory receptors on the surface of the NK cell, which bind to specific ligands on the surface of target cells. Among the activating receptors is a small class of specialized receptors termed the natural cytotoxicity receptors (NCRs) comprised of NKp30, NKp46, and NKp44. The NCRs are key receptors in the recognition and termination of virally infected and tumor cells. Since their discovery over 10 years ago, ligands corresponding to the NCRs have largely remained elusive. Recent identification of the cellular ligands for NKp44 and NKp30 as exosomal proliferating cell nuclear antigen (PCNA) and HLA-B-associated transcript 3 (BAT3), respectively, implicate that NCRs may function as receptors for damage-associated molecular pattern (DAMP) molecules. In this review, we focus on NKp44, which surprisingly recognizes two distinct ligands resulting in either activation or inhibition of NK cell effector responses in response to tumor cells. The inhibitory function of NKp44 requires further study as it may play a pivotal role in placentation in addition to being exploited by tumors as a mechanism to escape NK cell killing. Finally, we suggest that the NCRs are a class of pattern recognition receptors, which recognize signals of genomic instability and cellular stress via interaction with the c-terminus of DAMP molecules localized to the surface of target cells by various co-ligands.
NK cells; natural cytotoxicity receptors; NKp44; DAMPs; tumor ligands