Genomic regulation of immune response in neurodegeneration in mice

National Eye Institute

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Abstract

Cytokine regulation in helper T cells and innate lymphoid cells (ILCs) is essential for mounting an effective immune response, crucial for host defense. Dysregulated cytokine secretion can lead to autoimmunity. The specification of lymphocyte lineages and their cytokine production relies on the dynamic regulation of cis-regulatory elements. These elements involve multi-dimensional epigenetic mechanisms, including DNA methylation, chromatin accessibility, transcription factor binding, histone modifications, and DNA-DNA interactions that form chromatin loops. Our research delves into the development and dynamics of regulomes that control lymphocyte effector function, contributing to immune-related disorders. The three-dimensional chromatin architecture plays a pivotal role in determining the target of regulatory elements, which modulate the expression levels of thousands of genes, including those encoding cytokines. Interferon gamma (IFN-γ) and interleukin-22 (IL-22)-key cytokines dominating type 1 and type 3 immunity, respectively, are positioned near each other on the genome within an evolutionary synteny. These two cytokine genes are divergently regulated within two topologically associated domains (TADs), separated by a CTCF binding site. Deletion of the core CTCF site results in impaired IFN-γ production and aberrant IL-22 production in Th1 cells, due to dysregulated loop formation. Mice lacking this CTCF binding site exhibit dysregulated cytokine production and increased susceptibility to Toxoplasma gondii infection, highlighting the critical role of higher-order chromatin architecture in fine-tuning immune responses. Emerging evidence also suggests that lymphocytes play a crucial role during neurodegeneration. Using unbiased single-cell RNA-seq and flow cytometry approaches, our lab identified infiltrated CD8+ T cells in the brain parenchyma of amyloidosis mouse models. These cells exhibit type I interferon signatures, exacerbating Alzheimer’s disease-related phenotypes. Our recent research highlights the importance of modulating immune responses in control of neurodegeneration. Overall, our studies on gene regulation in immune cells, both in homeostasis and disease, have provided significant insights into important biological questions in the fields of immunology and neurodegeneration. This fundamental knowledge has opened new avenues for better disease prevention and treatment.