ABSTRACT
AIM2 is an interferon-inducible HIN-200 protein family member and is well-documented for its roles in innate immune responses as a DNA sensor. Recent studies have highlighted AIM2's function on regulatory T cells (Treg) and follicular T cells (Tfh). However, its involvement in Th17 cell differentiation remains unclear. This study reveals that AIM2 promotes Th17 cell differentiation. AIM2 deficiency decreases IL-17A production and downregulates key Th17 associated proteins (RORγt, IL-1R1, IL-23R). AIM2 is located in the nucleus of Th17 cells, where it interacts with RORγt, enhancing its binding to the Il17a promoter. The absence of AIM2 hinders naive CD4 T cells from differentiating into functional Th17 cells and from inducing colitis in Rag1-/- mice. This study uncovers AIM2's role as a regulator of Th17 cell transcriptional programming, highlighting its potential as a therapeutic target for Th17 cell-mediated inflammatory diseases.
ABSTRACT
Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms. Here, through a cellular and molecular characterization of meningeal γδ17 T cells, we defined the nearest central nervous system-associated source of IL-17a under homeostasis. Meningeal γδ T cells express high levels of the chemokine receptor CXCR6 and seed meninges shortly after birth. Physiological release of IL-17a by these cells was correlated with anxiety-like behavior in mice and was partially dependent on T cell receptor engagement and commensal-derived signals. IL-17a receptor was expressed in cortical glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice. Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates.
Subject(s)
Anxiety/etiology , Anxiety/metabolism , Interleukin-17/metabolism , Neurons/immunology , Neurons/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Animals , Anxiety/psychology , Behavior, Animal , Cell Proliferation , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Disease Models, Animal , Dura Mater , Gene Expression Profiling , Gene Expression Regulation , Interleukin-17/genetics , Meninges/immunology , Meninges/metabolism , Mice , Mice, Knockout , Receptors, Antigen, T-Cell, gamma-delta/genetics , Signal Transduction , TranscriptomeABSTRACT
Transforming Growth Factor ß (TGF-ß) is a multifunctional cytokine that plays a role in several biological processes. TGF-ß1 is the most abundantly expressed isoform, associated with susceptibility to various diseases, and several polymorphisms have been described in the TGF-ß1 gene structure, and some of them have been associated with functional implications. To date, eight single-nucleotide polymorphisms (SNPs) and one deletion/insertion polymorphism have been shown to affect TGF-ß1 expression (rs2317130, rs11466313, rs1800468, rs1800469, rs11466314, rs1800471, rs1800470, and rs11466316); some of these interfere with transcriptional regulation by affecting the binding of transcription factors binding, while others interfere with protein production. These polymorphisms have been associated with different types of diseases (i.e., cancers, cardiac diseases, inflammatory diseases, and others) and could therefore be used as susceptibility biomarkers. Since polymorphism clusters are likely to be more reliable than single polymorphisms in this respect, it is hoped that haplotype analysis of TGF-ß1 may reveal the genetic basis of disease susceptibility associated with the TGF-ß1 gene.
