Tissue adaptation of CD4 T lymphocytes in homeostasis and cancer.

The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression.

Changes in mitochondrial morphology modulate LPS-induced loss of calcium homeostasis in BV-2 microglial cells.

Microglial activation involves both fragmentation of the mitochondrial network and changes in cellular Ca2+ homeostasis, but possible modifications in mitochondrial calcium uptake have never been described in this context. Here we report that activated microglial BV-2 cells have impaired mitochondrial calcium uptake, including lower calcium retention capacity and calcium uptake rates. These changes were not dependent on altered expression of the mitochondrial calcium uniporter. Respiratory capacity and the inner membrane potential, key determinants of mitochondrial calcium uptake, are both decreased in activated microglial BV-2 cells. Modified mitochondrial calcium uptake correlates with impaired cellular calcium signaling, including reduced ER calcium stores, and decreased replenishment by store operated calcium entry (SOCE). Induction of mitochondrial fragmentation through Mfn2 knockdown in control cells mimicked this effect, while inhibiting LPS-induced mitochondrial fragmentation by a dominant negative form of Drp1 prevented it. Overall, our results show that mitochondrial fragmentation induced by LPS promotes altered Ca2+ homeostasis in microglial cells, a new aspect of microglial activation that could be a key feature in the inflammatory role of these cells.

Environmental Signals on Microglial Function during Brain Development, Neuroplasticity, and Disease.

Recent discoveries on the neurobiology of the immunocompetent cells of the central nervous system (CNS), microglia, have been recognized as a growing field of investigation on the interactions between the brain and the immune system. Several environmental contexts such as stress, lesions, infectious diseases, and nutritional and hormonal disorders can interfere with CNS homeostasis, directly impacting microglial physiology. Despite many encouraging discoveries in this field, there are still some controversies that raise issues to be discussed, especially regarding the relationship between the microglial phenotype assumed in distinct contexts and respective consequences in different neurobiological processes, such as disorders of brain development and neuroplasticity. Also, there is an increasing interest in discussing microglial-immune system cross-talk in health and in pathological conditions. In this review, we discuss recent literature concerning microglial function during development and homeostasis. In addition, we explore the contribution of microglia to synaptic disorders mediated by different neuroinflammatory outcomes during pre- and postnatal development, with long-term consequences impacting on the risk and vulnerability to the emergence of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders.

Fecal IgA Levels and Gut Microbiota Composition Are Regulated by Invariant Natural Killer T Cells.

BACKGROUND: The gut microbiota is a key element to support host homeostasis and the development of the immune system. The relationship between the microbiota and immunity is a 2-way road, in which the microbiota contributes to the development/function of immune cells and immunity can affect the composition of microbes. In this context, natural killer T cells (NKT cells) are distinct T lymphocytes that play a role in gut immunity and are influenced by gut microbes. In our work, we investigated the involvement of invariant NKT cells (iNKT) in intestinal homeostasis. RESULTS: We found that iNKT-deficient mice (iNKT-KO) had reduced levels of fecal IgA and an altered composition of the gut microbiota, with increased Bacteroidetes. The absence of iNKT cells also affected TGF-ß1 levels and plasma cells, which were significantly reduced in knockout (KO) mice. In addition, when submitted to dextran sodium sulfate colitis, iNKT-KO mice had worsening of colitis when compared with wild-type (WT) mice. To further address iNKT cell contribution to intestinal homeostasis, we adoptively transferred iNKT cells to KO mice, and they were submitted to colitis. Transfer of iNKT cells improved colitis and restored fecal IgA levels and gut microbiota. CONCLUSIONS: Our results indicate that intestinal NKT cells are important modulators of intestinal homeostasis and that gut microbiota composition may be a potential target in the management of inflammatory bowel diseases.

The role of glucose homeostasis on immune function in response to exercise: The impact of low or higher energetic conditions.

Immune cells are bioenergetically expensive during activation, which requires tightly regulated control of metabolic pathways. Both low and high glycemic conditions can modulate immune function. States of undernourishment depress the immune system, and in the same way, excessive intake of nutrients, such as an obesity state, compromise its functioning. Multicellular organisms depend on two mechanisms to survive: the regulation and ability to store energy to prevent starvation and the ability to fight against infection. Synergic interactions between metabolism and immunity affect many systems underpinning human health. In a chronic way, the breakdown of glycemic homeostasis in the body can influence cells of the immune system and consequently contribute to the onset of diseases such as type II diabetes, obesity, Alzheimer's, and fat and lean mass loss. On the contrary, exercise, recognized as a primary strategy to control hyperglycemic disorders, also induces a coordinated immune-neuro-endocrine response that acutely modulates cardiovascular, respiratory, and muscle functions and the immune response to exercise is widely dependent on the intensity and volume that may affect an immunodepressive state. These altered immune responses induced by exercise are modulated through the "stress hormones" adrenaline and cortisol, which are a threat to leukocyte metabolism. In this context, carbohydrates appear to have a positive acute response as a strategy to prevent depression of the immune system by maintaining plasma glucose concentrations to meet the energy demand from all systems involved during strenuous exercises. Therefore, herein, we discuss the mechanisms through which exercise may promotes changes on glycemic homeostasis in the metabolism and how it affects immune cell functions under higher or lower glucose conditions.

Innate lymphoid cells. New players in tissue homeostasis and inflammatory responses.

In recent times, our understanding of the role of the immune system in different physiopathological situations has increased markedly. A new set of cells, generically known as innate lymphoid cells (ILC), has been discovered in the lymphoid compartment. Five ILC subsets can be recognized according to phenotypic and functional similarities with different subpopulations of T lymphocytes. Unlike T and B lymphocytes, ILC do not express antigen receptors nor undergo selection and clonal expansion upon activation. Instead, they respond rapidly to cytokines and danger signals in infected or inflamed tissues, producing cytokines that direct the immune response toward a type suitable for controlling the initial insult. In addition, ILC establish a crosstalk with other cells of the microenvironment that contributes to the maintenance and restoration of tissue homeostasis. Although many evidences on ILC were obtained from animal models, solid data confirm their existence in humans and their role in various inflammatory disorders. In this article, we address new knowledge on ILC, particularly on their role in the homeostasis of the immune system and in various inflammatory pathologies, in order to present new actors regulating immunity and immunopathology and affecting human health.

En tiempos recientes, nuestra comprensión del rol del sistema inmune en diferentes situaciones fisiopatológicas ha aumentado notablemente. En el compartimiento linfoide se ha descubierto un conjunto de células denominadas células linfoides innatas o innate lymphoid cells (ILC). Las ILC incluyen cinco grupos, clasificados según su similitud fenotípica y funcional con diferentes subpoblaciones de linfocitos T. A diferencia de los linfocitos T y B, las ILC no expresan receptores de antígeno ni sufren selección y expansión clonal cuando se activan. En cambio, responden rápidamente frente a citoquinas y señales de peligro en tejidos infectados o inflamados produciendo citoquinas que dirigen la respuesta inmune hacia un tipo adecuado para controlar la noxa original. Además, las ILC establecen un diálogo cruzado con otras células del microambiente que contribuye al mantenimiento y la restauración de la homeostasis tisular. Si bien muchas evidencias acerca de las ILC fueron obtenidas en modelos animales, existen datos sólidos que confirman su existencia en seres humanos y su papel en diversos trastornos inflamatorios. En este artículo, abordamos los nuevos conocimientos acerca de las ILC, y su rol en la homeostasis del sistema inmune y en diversas patologías inflamatorias, con el fin de presentar nuevos actores que regulan la inmunidad y la inmunopatología, lo que repercute en la salud humana.

The multiple faces of CD5.

Since its discovery, over 30 years ago, CD5 has been used as a marker to identify T cells, B1-a cells, and B cell chronic lymphocytic leukemia cells. Throughout the years, many studies have described the functional relevance of CD5 as a modulator of T and B cell receptor signaling. However, it has not been until recent years that CD5 has emerged as a functional receptor in other areas of the immune system. Here, we review some of the most important aspects of CD5 as a modulator of TCR and BCR signaling, cell survival receptor both in T and B cells during health and disease, as well as the newly discovered roles of this receptor in thymocyte selection, T cell effector differentiation, and immune tolerance. CD5 was found to promote T cell survival by protecting autoreactive T cell from activation-induced cell death, to promote de novo induction of regulatory T cells in the periphery, to modulate Th17 and Th2 differentiation, and to modulate immune responses by modulating dendritic cell functions. CD5 is overexpressed in Tregs and Bregs, which are fundamental to maintain immune homeostasis. The newly established roles of CD5 in modulating different aspects of immune responses identify this receptor as an immune checkpoint modulator, and therefore it could be used as a target for immune intervention in different pathologies such as cancer, autoimmune diseases or infections.

Neuroautonomic activity evidences parturition as a complex and integrated neuro-immune-endocrine process.

Parturition in mammals demands a precise coordination of several neuro-immune-endocrine interactions including: a sterile inflammatory response that involves secretion of inflammation mediators like cytokines/chemokines; changes in the secretion of hormones such as progestogen, estrogens, cortisol, and oxytocin; as well as adjustments of the neuroautonomic function. Specifically, the so-called cholinergic anti-inflammatory pathway seems to play a key role in the homeostasis of the neuro-immune-endocrine axis by adjusting the vagus nerve activity during parturition. Here, we provide insights into the importance of the vagus during parturition from an autonomic, endocrine, and immune interplay perspective, and describe the potential role of heart rate variability analysis to explore these interactions noninvasively, economically, and accessibly.

Control of the inflammatory response during pregnancy: potential role of VIP as a regulatory peptide.

A network of cell-cell communications through contact and soluble factors supports the maternal-placental interaction and provides a suitable environment for fetal growth. Trophoblast cells take center stage at these loops: they interact with maternal leukocytes to sustain the varying demands of gestation, and they synthesize hormones, cytokines among other factors that contribute to the maintenance of immune homeostasis. Here, we discuss vasoactive intestinal peptide (VIP) and its potential as a regulatory neuropeptide in pregnancy. VIP is synthesized by trophoblast cells; it regulates trophoblast cell function and interaction with the major immune cell populations present in the pregnant uterus. VIP activity produces an anti-inflammatory microenvironment by modulating the functional profile of monocytes, macrophages, and regulatory T cells. Trophoblast VIP inhibits neutrophil extracellular trap formation and accelerates neutrophil apoptosis, enabling their silent clearance by phagocytic cells. The effects of VIP on the trophoblast-immune interaction are consistent with its regulatory role throughout pregnancy for immune homeostasis maintenance. These observations may provide new clues for pharmacological targeting of pregnancy complications associated with exacerbated inflammation.

Tissue macrophages as mediators of a healthy relationship with gut commensal microbiota.

Mammals and microorganisms have evolved a complex and tightly controlled mutual relationship. This interaction grants protection and energy source for the microorganisms, and on the other hand, provides several immunologic, metabolic and physiological advantages for the host. The gastrointestinal tract (GI) harbors the largest bacteria diversity within the body and complex mechanisms control microbiota community under homeostasis. However, once disrupted, microbiota imbalance can lead to overt growth of resident and invasive populations, with potential risk for lethal diseases. In these cases, bacteria might also escape from the intestines and reach different organs through the blood and lymphatic circulation. To control these unwanted conditions, all body tissues are populated with resident macrophages that have the ability to capture and eliminate pathogens, avoiding their dissemination. Here we discuss the different routes for bacterial translocation from the intestinal tract, and how macrophages act in the removal of these microorganisms to prevent systemic infections and restore the homeostasis.

Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation.

Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279).

[The role of gut microbiota in the regulation of the immune response]. / Rol de la microbiota gastrointestinal en la regulación de la respuesta inmune.

The gastrointestinal tract hosts around 10(14) bacterial microorganisms, in a constantly growing density from the stomach to the distal colon. This microbiota is composed by more than 500 species of bacteria, which are quickly acquired after birth, fairly stable during the host’s life, and essential for human homeostasis. These bacteria have important functions, such as stimulating the immune system, protecting the host from invading bacteria and viruses, and improving digestion, especially of complex carbohydrates. Also, the gut microbiota interacts directly with the immune system. However, the interaction of the intestinal epithelium and its microbiota with the immune system has yet to be fully understood. Secretory immunoglobulin A, produced by the plasma cells in Peyer’s patches and in the lamina propria, maintains non-invasive commensal bacteria and neutralize invasive pathogens. Dendritic cells migrate from the lamina propria of the secondary lymphoid organs to regulate gut immunity. They also have a key role maintaining luminal IgA and inducing the growth of regulatory T cells. Dendritic cells supervise the gut microenvironment too, keeping an immunological equilibrium and tolerance. The importance of the gut microbiota in regulating the immune system lies mostly in the homeostasis-or positive equilibrium. Thus, many diseases are a consequence of poor interactions or a loss of this equilibrium.

Biopatterned CTLA4/Fc Matrices Facilitate Local Immunomodulation, Engraftment, and Glucose Homeostasis After Pancreatic Islet Transplantation.

Pancreatic islet transplantation (PIT) represents a potential therapy to circumvent the need for exogenous insulin in type 1 diabetes. However, PIT remains limited by lack of donor islets and the need for long-term multidrug immunosuppression to prevent alloimmune islet rejection. Our goal was to evaluate a local immunoregulatory strategy that sustains islet allograft survival and restores glucose homeostasis in the absence of systemic immunosuppression. Nanogram quantities of murine CTLA4/Fc fusion protein were controllably delivered within human acellular dermal matrix scaffolds using an inkjet-based biopatterning technology and cotransplanted with allogeneic islets under the renal capsule to create an immunoregulatory microenvironment around the islet allograft. We achieved long-term engraftment of small loads of allogeneic islet cells with 40% of MHC-mismatched mouse recipients maintaining sustained normoglycemia following pancreatic ß-cell ablation by streptozotocin. Biopatterned CTLA4/Fc local therapy was associated with expansion of Foxp3+ regulatory T cells and shifts in cytokine production and gene expression from proinflammatory to regulatory profiles, thus substantially benefiting islet allografts survival and function. This study is a new paradigm for targeted therapies in PIT that demonstrates the favorable effects of immune alterations in the transplant milieu and suggests a unique strategy for minimizing systemic immunosuppression and promoting islet allograft survival.

Rol de la microbiota gastrointestinal en la regulación de la respuesta inmune / The role of gut microbiota in the regulation of the immune response

The gastrointestinal tract hosts around 10(14) bacterial microorganisms, in a constantly growing density from the stomach to the distal colon. This microbiota is composed by more than 500 species of bacteria, which are quickly acquired after birth, fairly stable during the host’s life, and essential for human homeostasis. These bacteria have important functions, such as stimulating the immune system, protecting the host from invading bacteria and viruses, and improving digestion, especially of complex carbohydrates. Also, the gut microbiota interacts directly with the immune system. However, the interaction of the intestinal epithelium and its microbiota with the immune system has yet to be fully understood. Secretory immunoglobulin A, produced by the plasma cells in Peyer’s patches and in the lamina propria, maintains non-invasive commensal bacteria and neutralize invasive pathogens. Dendritic cells migrate from the lamina propria of the secondary lymphoid organs to regulate gut immunity. They also have a key role maintaining luminal IgA and inducing the growth of regulatory T cells. Dendritic cells supervise the gut microenvironment too, keeping an immunological equilibrium and tolerance. The importance of the gut microbiota in regulating the immune system lies mostly in the homeostasis-or positive equilibrium. Thus, many diseases are a consequence of poor interactions or a loss of this equilibrium.

Impact of Human Mutant TGFß1/Fc Protein on Memory and Regulatory T Cell Homeostasis Following Lymphodepletion in Nonhuman Primates.

Transforming growth factor ß1 (TGFß1) plays a key role in T cell homeostasis and peripheral tolerance. We evaluated the influence of a novel human mutant TGFß1/Fc (human IgG4 Fc) fusion protein on memory CD4+ and CD8+ T cell (Tmem) responses in vitro and their recovery following antithymocyte globulin (ATG)-mediated lymphodepletion in monkeys. TGFß1/Fc induced Smad2/3 protein phosphorylation in rhesus and human peripheral blood mononuclear cells and augmented the suppressive effect of rapamycin on rhesus Tmem proliferation after either alloactivation or anti-CD3/CD28 stimulation. In combination with IL-2, the incidence of CD4+ CD25hi Foxp3hi regulatory T cells (Treg) and Treg:Th17 ratios were increased. In lymphodepleted monkeys, whole blood trough levels of infused TGFß1/Fc were maintained between 2 and 7 µg/mL for 35 days. Following ATG administration, total T cell numbers were reduced markedly. In those given TGFß1/Fc infusion, CD8+ T cell recovery to predepletion levels was delayed compared to controls. Additionally, numbers of CD4+ CD25hi CD127lo Treg increased at 4-6 weeks after depletion but subsequently declined to predepletion levels by 12 weeks. In all monkeys, CD4+ CD25hi Foxp3hi Treg/CD4+ IL-17+ cell ratios were reduced, particularly after stopping TGFß1/Fc infusion. Thus, human TGFß1/Fc infusion may delay Tmem recovery following lymphodepletion in nonhuman primates. Combined (low-dose) IL-2 infusion may be required to improve the Treg:Th17 ratio following lymphodepletion.

The multifaceted role of commensal microbiota in homeostasis and gastrointestinal diseases.

The gastrointestinal tract houses a complex and diverse community of microbes. In recent years, an increased understanding of the importance of intestinal microbiota for human physiology has been gained. In the steady state, commensal microorganisms have a symbiotic relationship with the host and possess critical and distinct functions, including directly influencing immunity. This means that recognition of commensal antigens is necessary for the development of complete immune responses. Therefore, the immune system must face the challenge of maintaining mucosal homeostasis while dealing with undue passage of commensal or pathogenic microbes, as well as the host nutritional status or drug use. Disruption of this fine balance has been associated with the development of several intestinal inflammatory diseases. In this review, we discuss the mechanisms involved in the modulation of host-microbe interactions and how the breakdown of this homeostatic association can lead to intestinal inflammation and pathology.

Restoring host-microbe homeostasis via selective chemoattraction of Tregs.

The disruption of host-microbe homeostasis at the site of periodontal disease is considered a key factor for disease initiation and progress. While the downstream mechanisms responsible for the tissue damage per se are relatively well-known (involving various patterns of immune response operating toward periodontal tissue destruction), we are only beginning to understand the complexity of host-microbe interactions in the periodontal environment. Unfortunately, most of the research has been focused on the disruption of host-microbe homeostasis instead of focusing on the factors responsible for maintaining homeostasis. In this context, regulatory T-cells (Tregs) comprise a CD4+FOXp3 +T-cell subset with a unique ability to regulate other leukocyte functions to avoid excessive immune activation and its pathological consequences. Tregs act as critical determinants of host-microbe homeostasis, as well as determinants of a balanced host response after the disruption of host-microbe homeostasis by pathogens. In periodontitis, Tregs play a protective role, with their natural recruitment being responsible for conversion of active into inactive lesions. With controlled-release technology, it is now possible to achieve a selective chemoattraction of Tregs to periodontal tissues, attenuating experimental periodontitis evolution due to the local control of inflammatory immune response and the generation of a pro-reparative environment.

Contribution of vasoactive intestinal peptide to immune homeostasis in trophoblast-maternal leukocyte interaction under LPS stimulation.

BACKGROUND/AIMS: The maternal-fetal interface is a unique immunological site that generates an adequate microenvironment during pregnancy, recognizing and eliminating infections and tolerating the trophoblast/placenta unit. For that purpose, trophoblast cells display several tolerogenic mechanisms to allow fetal survival, such as production of the neuropeptide vasoactive intestinal peptide (VIP). Here we investigated the contribution of VIP to maintain homeostasis at the maternal-placental interface under lipopolysaccharide (LPS) stimulation. METHODS: We performed cocultures between trophoblast cells (Swan-71 cell line) and maternal leukocytes obtained from fertile women as an in vitro model of maternal-placental interaction, and we focused on the effects of LPS on the modulation of VIP and their receptors (VPAC1 and VPAC2). RESULTS: VIP could prevent the upregulation of IL-6, MCP-1, and nitrite production and maintain the production of IL-10 and TGF-ß under LPS (10 µg/ml) stimulation after 48 h of coculture. To gain deeper insight into the mechanisms of how VIP could contribute to a tolerogenic microenvironment even in the presence of LPS, we investigated VIP production by maternal leukocytes and observed a significant increase in the frequency of CD4+VIP+ cells after interaction with Swan-71 cells in the presence of LPS. LPS increased VIP and inducible receptor VPAC2 expression directly on trophoblast cells in a dose- and time-dependent manner. CONCLUSIONS: The present results suggest that VIP might act as an additional homeostatic mechanism during early stages at the maternal-placental interface to control exacerbated inflammatory responses such as the ones observed in intrauterine infections.

[Autophagy and immune response]. / Autofagia y respuesta inmunitaria.

Autophagy is a complex process in which cell homeostasis of proteins, organelles, exocitic and endocitic vacuoles are controlled. There is a direct link between autophagy and cell death with antigen processing, generation of inflammatory response and immune response. In different diseases, deficiencies in autophagy have been reported. It has been proposed that in early stages of cancer, autophagy is capable of inducing cell death; however, in agresive tumors and metastasis, the process is responsible for pharmacologic resistance and tumor survival. More research has to be done in order to allow us to understand the process and generate therapeutic options in different pathologies important for the human being.