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. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

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). Specific Treg cell differentiation and activation states have been linked to several human diseases. Indeed, Treg cells play a crucial role in different diseases including colitis, multiple sclerosis, autoimmunity, and infection. Characterization of Treg cell functions and understanding the role of different Treg cell subsets are crucial to the development of novel Treg cell-specific therapeutics for inflammatory diseases. In this phenotype report, we will describe laboratory methods to effectively study and characterize human Treg cells.

A common IL-4 receptor variant promotes asthma severity via a Treg 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 (Treg ) cells in an IL-6-dependent manner. OBJECTIVE: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on Treg cells as a function of IL4RR576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on Treg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. RESULTS: Asthmatics carrying the IL4RR576 allele had increased Notch4 expression on their circulating Treg cells as a function of disease severity and serum IL-6. Mice harboring the Il4raR576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon Treg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung Treg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor. CONCLUSION: These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung Treg cell function.

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. Under inflammatory conditions, Foxp3+ Treg cells may acquire effector T cell programs that modify their phenotype and function, reflecting their plasticity. During microbial infections, Treg cells act to limit the immunopathology triggered by the host immune response to pathogens albeit at the potential risk of pathogen persistence. In this review, we will discuss the influence of Treg cells on the outcome of viral infection and will give an overview of the Treg phenotype at steady-state and in inflammatory conditions.

Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-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 outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.