The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages.

Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities.

Exclusive enteral nutrition impacts peripheral blood mononuclear cell profile of children with Crohn's disease.

The immunological effects of exclusive enteral nutrition (EEN) in the treatment of active Crohn's disease (CD) are yet to be unveiled. The present study investigated changes in peripheral blood mononuclear cell profiles in children with active CD following 8-week treatment with EEN. In nine children, EEN significantly decreased the number and frequency of circulating effector memory CD8+ T cells re-expressing CD45RA, with corresponding increases observed in the frequency of circulating central and effector memory CD8+ T cells. These signals were conserved when looking at a subgroup of patients who achieved remission, and another who demonstrated the highest level of compliance to EEN. We speculate that the increases in circulating central and effector memory CD8+ T cells may be related to the extensive microbiome-modifying effects of EEN dampening immune response within the gastrointestinal tract.

CD11c identifies microbiota and EGR2-dependent MHCII+ serous cavity macrophages with sexually dimorphic fate in mice.

The murine serous cavities contain a rare and enigmatic population of short-lived F4/80lo MHCII+ macrophages but what regulates their development, survival, and fate is unclear. Here, we show that mature F4/80lo MHCII+ peritoneal macrophages arise after birth, but that this occurs largely independently of colonization by microbiota. Rather, microbiota specifically regulate development of a subpopulation of CD11c+ cells that express the immunoregulatory cytokine RELM-α, are reliant on the transcription factor EGR2, and develop independently of the growth factor CSF1. Furthermore, we demonstrate that intrinsic expression of RELM-α, a signature marker shared by CD11c+ and CD11c- F4/80lo MHCII+ cavity macrophages, regulates survival and differentiation of these cells in the peritoneal cavity in a sex-specific manner. Thus, we identify a previously unappreciated diversity in serous cavity F4/80lo MHCII+ macrophages that is regulated by microbiota, and describe a novel sex and site-specific function for RELM-α in regulating macrophage endurance that reveals the unique survival challenge presented to monocyte-derived macrophages by the female peritoneal environment.

Monocytes mediate Salmonella Typhimurium-induced tumor growth inhibition in a mouse melanoma model.

The use of bacteria as an alternative cancer therapy has been reinvestigated in recent years. SL7207: an auxotrophic Salmonella enterica serovar Typhimurium aroA mutant with immune-stimulatory potential has proven a promising strain for this purpose. Here, we show that systemic administration of SL7207 induces melanoma tumor growth arrest in vivo, with greater survival of the SL7207-treated group compared to control PBS-treated mice. Administration of SL7207 is accompanied by a change in the immune phenotype of the tumor-infiltrating cells toward pro-inflammatory, with expression of the TH 1 cytokines IFN-γ, TNF-α, and IL-12 significantly increased. Interestingly, Ly6C+ MHCII+ monocytes were recruited to the tumors following SL7207 treatment and were pro-inflammatory. Accordingly, the abrogation of these infiltrating monocytes using clodronate liposomes prevented SL7207-induced tumor growth inhibition. These data demonstrate a previously unappreciated role for infiltrating inflammatory monocytes underlying bacterial-mediated tumor growth inhibition. This information highlights a possible novel role for monocytes in controlling tumor growth, contributing to our understanding of the immune responses required for successful immunotherapy of cancer.

Can we treat inflammation by managing misbehaving monocytes?

When monocytes migrate from blood into tissues they differentiate into macrophage-like cells. The outcome of this differentiation process is strongly influenced by the tissue environment, and the macrophages produced help control the immunological properties of the tissue. The process of monocyte-macrophage differentiation is therefore potentially attractive when seeking therapeutic targets to amplify or modulate the inflammatory response. Here we highlight recent research in this area, identifying the gene Paqr11 as an important factor in monocyte differentiation, and therefore an important potential target for reducing macrophage-mediated inflammation in arthritis.

Sensitive detection of anti-spike antibodies enables improved understanding of SARS-CoV-2 pathogenesis.

Mass vaccination of the global population against SARS-CoV-2 will, we hope, turn the tide against this devastating pandemic. To complement vaccinations, better tools are needed to enable viral infections and immunological protection to be monitored. Accurate tools provide sound data for informed decision-making at many levels, from personal to governmental. The measurement of viral RNA is currently routinely used to detect active infections, but only gives a positive result during infection and is unable to reveal historic infections. Tests involving a detection of SARS-CoV-2-specific antibodies can reveal prior exposures to virus and can measure anti-viral immune responses induced after natural infection or after vaccination. They may eventually also be used to predict an individual's likelihood of becoming re-infected. Here, we report on the development of a sensitive ELISA technique to detect multiple isotypes of antibodies against the spike glycoprotein, in samples of both serum and saliva. This paper provides an important step towards understanding the immune response to SARS-CoV-2 and may therefore eventually help us to effectively control it.

Beyond cytokines: Influences of the endocrine system on human immune homeostasis.

The immune system must be tightly controlled to prevent potentially damaging over-response to pathogens and must also be actively maintained in a responsive state when no immediate threat is present. These processes of control and maintenance are important for sustaining a state of immune homeostasis and are controlled by a network of cellular and molecular interactions. Here, we highlight a recent publication in Immunology (2021) where the authors have examined the effects of the thyroid and pituitary hormones, thyrotrophin and thyroxine, on immune homeostasis in humans. This work reveals homeostatic effects of these hormones on T cells and B cells and raises the possibility that the endocrine system might be manipulated to modulate the immune response.

The importance of polyreactive antibodies in protection against pneumococcal infection.

Antibodies are a key element of the immune response. They can bind their molecular targets with exquisite sensitivity and specificity, providing protection against a multitude of pathogens. They have long been understood to be markers of a successful response to vaccination, and are now widely manufactured as highly specific and robust immunotherapeutic agents. Less well understood are the polyreactive antibodies, found in serum, which are able to bind more than one target molecule. Here, we highlight new research into these naturally occurring polyreactive antibodies, which demonstrates their importance for protection against Streptococcus pneumoniae, a common cause of airway infection.

Teaching tolerance: Diverse cellular interactions enable healthy maturation.

The fetal immune system is distinguishable from the adult immune system by a higher degree of tolerance to foreign antigens. This tolerance is important for fetal development within the 'foreign' maternal environment, and during birth when barrier surfaces are first colonized by microbiota. Immune responses against the wave of newly colonizing microbiota would cause massive damage to barrier tissues, so neonates need suppressed immune responses and instead rely on maternal antibodies for protection. It is becoming clear that the early-life establishment of tolerance could impact immune homeostasis and predisposition to autoimmune diseases throughout life. However, it is not well understood how and when perinatal tolerogenic immune responses switch towards adult-like effector immune responses. Here, we present a new report on the differences between cells from perinatal umbilical cord blood (UCB) and adult peripheral blood mononuclear cells (PBMC), which give mechanistic insights into fetal tolerogenic responses.

Do peripheral protein oligomers in neurodegenerative diseases shape T cell responses beyond the brain?

Neurodegenerative diseases place a devastating burden on affected individuals and their families, and new treatments are desperately needed for these common immune-mediated inflammatory conditions. While large aggregates of abnormal proteins in the brain cause significant damage, it is becoming clear that smaller soluble protein aggregates can also contribute to disease, by both direct and indirect mechanisms. These soluble protein oligomers can be found in patients' serum. Here, we describe recent research that identifies effects of model oligomer molecules on peripheral blood T cells, therefore providing an additional mechanism by which neurodegeneration may be worsened through amplification of peripheral adaptive immune responses.

A retrospective view of 2020: A unique year for Immunology.

2020 was a year unlike any other for Immunology. Through the SARS-CoV-2 pandemic, with fantastic support from the global immunology community, we worked together to reach new heights. Here, we look back at some of the highlights for Immunology in a challenging and memorable year.

Dietary triggers of gut inflammation following exclusive enteral nutrition in children with Crohn's disease: a pilot study.

BACKGROUND: The anti-inflammatory effect of exclusive enteral nutrition on the gut of children with Crohn's disease is rapidly lost after food reintroduction. This study assessed disease dietary triggers following successful treatment with exclusive enteral nutrition. METHODS: Nutrient intake, dietary patterns and dietary biomarkers in faeces (gluten immunogenic peptides, undigestible starch, short chain fatty acids) were assessed in 14 children with Crohn's disease during early food reintroduction, following exclusive enteral nutrition. Groups above (Group A) and below (Group B) the median levels of faecal calprotectin after food reintroduction were assigned for comparative analysis. RESULTS: Intakes of fibre, gluten-containing cereals and red and processed meat were significantly higher in Group A than Group B; (median [Q1, Q3], g/day; Fibre: 12.1 [11.2, 19.9] vs. 9.9 [7.6, 12.1], p = 0.03; Red and processed meat: 151 [66.7, 190] vs. 63.3 [21.7, 67], p = 0.02; gluten-containing cereals: 289 [207, 402] vs. 203 [61, 232], p = 0.035). A diet consisting of cereals and meat products was predictive (92% accuracy) of higher faecal calprotectin levels after food reintroduction. In faeces, butyrate levels, expressed as absolute concentration and relative abundance, were higher in Group A than Group B by 28.4 µmol/g (p = 0.015) and 6.4% (p = 0.008), respectively. Levels of gluten immunogenic peptide and starch in faeces did not differ between the two groups. CONCLUSIONS: This pilot study identified potential dietary triggers of gut inflammation in children with Crohn's disease after food reintroduction following treatment with exclusive enteral nutrition. TRIAL REGISTRATION: Clinical trials.gov registration number: NCT02341248; Clinical trials.gov URL: https://clinicaltrials.gov/ct2/show/NCT02341248 (retrospectively registered).

Salmonella enterica Serovar Typhimurium Travels to Mesenteric Lymph Nodes Both with Host Cells and Autonomously.

Salmonella infection is a globally important cause of gastroenteritis and systemic disease and is a useful tool to study immune responses in the intestine. Although mechanisms leading to immune responses against Salmonella have been extensively studied, questions remain about how bacteria travel from the intestinal mucosa to the mesenteric lymph nodes (MLN), a key site for Ag presentation. In this study, we used a mouse model of infection with Salmonella enterica serovar Typhimurium (STM) to identify changes in intestinal immune cells induced during early infection. We then used fluorescently labeled STM to identify interactions with immune cells from the site of infection through migration in lymph to the MLN. We show that viable STM can be carried in the lymph by any subset of migrating dendritic cells but not by macrophages. Moreover, approximately half of the STM in lymph are not associated with cells at all and travel autonomously. Within the MLN, STM associates with dendritic cells and B cells but predominantly with MLN-resident macrophages. In conclusion, we describe the routes used by STM to spread systemically in the period immediately postinfection. This deeper understanding of the infection process could open new avenues for controlling it.

It's time to think about circadian rhythms.

We here introduce a Review Series focussing on the important influences circadian rhythms have on immune responses. The three reviews in this series, expertly curated by Rachel Edgar, discuss how the cyclic oscillations in our cellular clock affect the innate and adaptive immune response, and how interactions with the intestinal microbiota, themselves subject to daily oscillations, also influence immune responses. As we understand more about these mechanisms, by which chronobiology contributes to immunology, it is becoming increasingly clear that they have important functions in maintaining health, influence autoimmunity and may contribute to the effectiveness of vaccinations.

From functions to mechanisms of the prototypic complement C5 antibody BB5.1.

Antibodies that bind complement components were first identified over 30 years ago. Investigations into their functions in animal models motivated clinical studies that have now generated licensed products and a strong pipeline of future therapeutics. Despite this, the mechanisms of action of one of the first effective C5-binding antibodies, BB5.1, were not known. Here, we report a new study that reveals these mechanisms, enabling new approaches for designing C5-binding molecules for therapeutic use.

Ageing dangerously; homing of senescent CD8 T cells in cutaneous Leishmaniasis.

Both CD8+ T cells and NK cells contribute to the immune response against the protozoan Leishmania parasite. Both are able to generate IFN-γ and both display cytotoxic features. These features may enable them to not only contribute to parasite clearance but also to cause immune-mediated pathology. This pathology is evident, for example, in the Leismania-induced skin lesions found in patients with cutaneous leismaniasis (CL). Here we highlight new data demonstrating that CD8+ T cells and NK cells in CL display a highly cytotoxic senescent phenotype, and that the senescent T cells play a major role in mediating skin pathology. This is the first demonstration that senescent CD8 T cells contribute to immunopathology in vivo.

T cells and cytokines in inflamed psoriatic skin. Who's in charge?

Inflammation in psoriasis is driven through the IL-23/IL-17 pathway. Monoclonal antibodies targeting cytokines in the pathway have proven highly effective and are widely used in clinical practice. There is still much to learn, however, about how these pathogenic responses are controlled, particularly with respect to the highly immunologically active molecules produced by the inflamed skin tissue itself. These tissue-derived molecules, which include IL-33, play important roles in modulating chronic inflammation that we are only beginning to understand. Here we highlight new research indicating a role for IL-33 in modulating the inflammatory Th17 response in psoriasis, which may provide avenues for developing new psoriasis treatments.

Recovery training or over-training? The contribution of TLR10 to monocyte fitness.

The concept of trained immunity refers to remodelling of the monocyte and macrophage metabolic and epigenetic landscape, conferring an amplified inflammatory response upon secondary stimulation. This effect is typically modelled in vitro by stimulating monocytes with either Bacillus Calmette Guerin (BCG) or ß-Glucan for 24 hr, before subsequent stimulation with LPS or Pam-3-Cys (P3C) as a secondary stimulus 6 days later. Here, we focus on a recent paper which interrogated the role of the anti-inflammatory TLR, TLR10, on trained immunity. Using both an in vitro model of trained immunity, and analysis of BCG vaccinated individuals, the authors interestingly demonstrate that, despite its ability to regulate aspects of innate immunity, TLR10 does not have a significant role in this process.

Should we be more cre-tical? A cautionary tale of recombination.

The cre-loxP system has been revolutionary in the field of immunology. The technology enables genetic deletion in mice with unprecedented precision. It is therefore now widely used to investigate gene functions in animal models of disease, and in fundamental studies of the immune response. This widespread adoption of cre-loxP technology has allowed a thorough investigation of its strengths and weaknesses. Here we highlight an important paper which not only describes potential problems with the commonly-used screening procedures used when identifying offspring of the correct genotype, but also describes how this screening can be improved to ensure that the right animals are produced.

Guide to Immunopharmacology: a database to boost immunology education, research and therapy.

In the era of big data, the establishment of a free database, containing all the immune drug targets and associated cell types, is of great value. To this aim, the Guide to Immunopharmacology has been created in a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) and the International Union of Immunological Societies (IUIS). Here we highlight the structure and content of the database, which includes up-to-date quantitative information on the fundamental science underlying each immune target. A set of practical examples and tools for data mining are summarized to support immune research into drug discovery and therapeutics.