Genomic regulation of immune response in neurodegeneration in mice

National Eye Institute

Investigators

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Abstract

Cytokine regulation in helper T and innate lymphoid cells (ILCs) is critical to mount a proper immune response for host defense. Dysregulated cytokine secretion leads to autoimmunity. The specification of lymphocyte lineages and their cytokine production relies on dynamic regulation of cis-regulatory elements that involve multi-dimensional epigenetic mechanisms, including DNA methylation, chromatin accessibility, transcription factor binding, histone modification and DNA-DNA interactions that form chromatin loops. Our work explores the development and dynamics of regulomes that control lymphocyte effector function that contribute to immune-related disorders. ILCs play critical roles in pathogen defense and tissue homeostasis, but our knowledge in their heterogeneity is relatively poor. Recently, our collaborative work with the Scium lab (Sapienza University of Rome) revealed two markers, Granzyme A and CD160, that can delineate ILC1 subsets with distinct effector functions (Di Censo et al., Eur J Immunol. 2021). Unlike NK cells, liver-specific GzmA+CD160- ILC1s require minimal JAK/STAT signals and the transcription factor Nfil3, despite the preservation of cytotoxicity. These findings provide insights for regulation of innate responses and new targets for immunomodulation. These findings along with others have been summarized in our recent review articles (Fernando et al., Frontiers in Immunology, 2021, Scott-Browne et al., Immunol Rev. 2022). Epigenetic modulation is also involved in a variety of biological events. For example, patients with activated phosphatidylinositol 3-kinase delta (PI3K) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. In collaboration with Schwartsberg Lab (NIAID), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of effector populations both in vitro and after viral infection with an altered chromatin landscape. Our data position PI3K as integrating multiple signaling nodes that promote CD8+ T cell effector differentiation, providing insight into phenotypes of patients with APDS (Cannons et al., Cell Rep, 2021). Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. In collaboration with Wu and Lenardos Labs (NCI and NIAID), we showed epigenetic alterations in St6galnac1 mutant crypt intestinal stem cells that results in compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation (Yao et al., Cell, 2021). Epigenetic imprinting also plays an essential role during fetal development. In collaboration with the Belkaid lab (NIAID), we recently showed that the cytokine IL-6 mediated chromatin remodeling in the fetal intestinal epithelium, in which the mom was infected by a food-borne pathogen Yersinia pseudotuberculosis during pregnancy (Lim et al., Science, 2021). This finding highlights the importance of prenatal immune education. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), are recently appreciated as critical regulators in epigenetic immunomodulation. Using an engineered mouse model, our recent collaborative work with the OShea lab (NIAMS) revealed roles of miR-221/222 in regulating type 3 helper T (Th17) cells (Mikami et al., Immunity, 2021). Depletion of miR-221/222 up-regulates gene expression of c-Maf, a critical transcription factor for Th17, and the IL-23 receptor, which results in hyper-responsibility to a pro-inflammatory cytokine IL-23 and greater susceptibility of DSS-induced colitis. These findings along with others have been summarized in our recent review articles (Morrison et al., Cold Spring Harb Perspect Biol. 2021). In sum, our studies in gene regulation have significantly answered important biological questions in the fields of development and immunology. This fundamental knowledge has created new avenues for better disease prevention and treatment.