RELMβ sets the threshold for microbiome-dependent oral tolerance.

Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule β (RELMβ) is a critical regulator of oral tolerance.

Notch4 regulatory T cells and SARS-CoV-2 viremia shape COVID19 survival outcome.

Background: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear.

Methods: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022.

Pathogenic mechanisms in the evolution of food allergy.

The early development of the neonatal immune system is profoundly influenced by exposure to dietary and microbial antigens, which shapes mucosal tolerance. Successful oral tolerance induction is crucially dependent on microbially imprinted immune cells, most notably the RORγt regulatory T (Treg) and antigen presenting cells and is essential for preventing food allergy (FA). The development of FA can be envisioned to result from disruptions at key checkpoints (CKPTs) that govern oral tolerance induction.

The Impact of Russia-Ukraine geopolitical conflict on the air quality and toxicological properties of ambient PM in Milan, Italy.

The geopolitical conflict between Russia and Ukraine has disrupted Europe's natural gas supplies, driving up gas prices and leading to a shift towards biomass for residential heating during colder months. This study assessed the consequent air quality and toxicological impacts in Milan, Italy, focusing on fine particulate matter (PM, d < 2.5 μm) emissions.

Age-specific Metabolomic profiles in children with food allergy.

Background: Food allergy (FA) in young children is often associated with eczema, frequently directed to egg/cow milk allergens and has a higher chance of resolution, while FA that persists in older children has less chance of resolution and is less clearly associated with atopy.

Methods: Children with FA (n = 62) and healthy controls (n = 28) were categorized into "younger" (≤5 years) and "older" (>5 years). Mass spectrometry-based untargeted metabolomic profiling as wells as cytokine profiling were performed on plasma samples in FA children in each age group.

Regulatory T cells in allergic inflammation.

Regulatory T (Treg) cells maintain immune tolerance to allergens at the environmental interfaces in the airways, skin and gut, marshalling in the process distinct immune regulatory circuits operative in the respective tissues. Treg cells are coordinately mobilized with allergic effector mechanisms in the context of a tissue-protective allergic inflammatory response against parasites, toxins and potentially harmful allergens, serving to both limit the inflammation and promote local tissue repair. Allergic diseases are associated with subverted Treg cell responses whereby a chronic allergic inflammatory environment can skew Treg cells toward pathogenic phenotypes that both perpetuate and aggravate disease.

Regulatory T cells in dominant immunologic tolerance.

Regulatory T cells expressing the transcription factor forkhead box protein 3 mediate peripheral immune tolerance both to self-antigens and to the commensal flora. Their defective function due to inborn errors of immunity or acquired insults is associated with a broad range of autoimmune and immune dysregulatory diseases. Although their function in suppressing autoimmunity and enforcing commensalism is established, a broader role for regulatory T cells in tissue repair and metabolic regulation has emerged, enabled by unique programs of tissue adaptability and specialization.

The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice.

Background: Atopic dermatitis (AD) is characterized by T2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The T2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity.

Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis.

T peripheral helper (Tph) cells, identified in the synovium of adults with seropositive rheumatoid arthritis, drive B cell maturation and antibody production in non-lymphoid tissues. We sought to determine if similarly dysregulated T cell-B cell interactions underlie another form of inflammatory arthritis, juvenile oligoarthritis (oligo JIA). Clonally expanded Tph cells able to promote B cell antibody production preferentially accumulated in the synovial fluid (SF) of oligo JIA patients with antinuclear antibodies (ANA) compared to autoantibody-negative patients.

Regulatory T-cells in asthma.

Purpose Of Review: This review addresses recent progress in our understanding of the role of regulatory T (Treg) cells in enforcing immune tolerance and tissue homeostasis in the lung at steady state and in directing the immune response in asthmatic lung inflammation.

Recent Findings: Regulatory T cells regulate the innate and adaptive immune responses at steady state to enforce immune tolerance in lung tissues at steady state and their control of the allergic inflammatory responses induced by allergens. This regulatory function can break down in the context of chronic asthmatic airway inflammation such that the lung tissue Treg cells become skewed towards a pathogenic phenotype that aggravates and perpetuates disease.

The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation.

CPHEN-016: Comprehensive phenotyping of human regulatory T cells.

Peripheral immunological tolerance is mainly maintained by regulatory T (Treg) cells, a specific CD4 T cells subset that expresses the transcription factor Foxp3. Treg cells are crucial to control autoimmunity and inflammation and to limit tissue destruction arising from inflammatory responses. Loss of functions mutations in FOXP3 in humans induces a fatal autoimmune lymphoproliferative disorder, known as Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX).

A Stk4-Foxp3-NF-κB p65 transcriptional complex promotes T cell activation and homeostasis.

The molecular programs involved in regulatory T (T) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in T cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4-NF-κB p65-Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418.

SARS-CoV-2-specific T cell responses in patients with multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11-2 that was not associated with HLA genotype.

Microbiome, Metabolism, and Immunoregulation of Asthma: An American Thoracic Society and National Institute of Allergy and Infectious Diseases Workshop Report.

This report presents the proceedings from a workshop titled "Microbiome, Metabolism and Immunoregulation of Asthma" that was held virtually May 13 and 14, 2021. The workshop was jointly sponsored by the American Thoracic Society (Assembly on Allergy, Immunology, and Inflammation) and the National Institute of Allergy and Infectious Diseases. It convened an interdisciplinary group of experts with backgrounds in asthma immunology, microbiome science, metabolomics, computational biology, and translational pulmonary research.

A common IL-4 receptor variant promotes asthma severity via a T cell GRB2-IL-6-Notch4 circuit.

Background: The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (T ) cells in an IL-6-dependent manner.

Objective: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation.

Genetic tracing reveals transcription factor Foxp3-dependent and Foxp3-independent functionality of peripherally induced Treg cells.

Regulatory T (Treg) cells expressing the transcription factor Foxp3 are an essential suppressive T cell lineage of dual origin: Foxp3 induction in thymocytes and mature CD4 T cells gives rise to thymic (tTreg) and peripheral (pTreg) Treg cells, respectively. While tTreg cells suppress autoimmunity, pTreg cells enforce tolerance to food and commensal microbiota. However, the role of Foxp3 in pTreg cells and the mechanisms supporting their differentiation remain poorly understood.

CPHEN-014: Comprehensive phenotyping of mouse regulatory T cells relevant to viral infections.

Regulatory T (Treg) cells are a specialized subpopulation of CD4 T cells that enforce peripheral immune tolerance. Treg cells act to suppress exuberant immune responses, limit inflammation, and promote tissue repair, thereby maintaining homeostasis and tolerance to self-antigens and those of the commensal microbial flora. Treg cells are characterized by the expression of the master regulator Foxp3, which plays a major role in Treg cells development and function.

Atopic Dermatitis Mediates the Association Between an IL4RA Variant and Food Allergy in School-Aged Children.

Background: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests.

Objective: To test the hypothesis that AD mediates the relationship between an IL-4 receptor alpha chain gene (IL4RA) variant, the human IL-4 receptor alpha chain protein-R576 polymorphism, and FA.