Cytokine signaling, immunoregulation and autoimmune disease

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

Cytokines regulate cellular growth and differentiation, hematopoiesis, metabolism, and tissue repair. These factors are also critical in host defense including viral infection but are also major contributors to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, lupus, IBD, alopecia areata and psoriasis, as well as allergy and asthma. This underscores the need to better understand the molecular basis of cytokine action and the regulation of cytokine expression to better understand mechanisms of diverse diseases and improve treatment. A critical family of cytokines are those that use the JAK-STAT pathway; the role of this pathway in cytokine signaling has been a central interest of the lab for multiple decades. Several advances we made this year include regulation of immunometabolism by cytokines. It has been well known that activated lymphocytes adapt their metabolism to meet the energetic and biosynthetic demands imposed by rapid growth and proliferation in which a cytokine IL-2 plays a central role to support T cell proliferation. We investigated metabolome and transcriptome of IL-2-STAT5 modulated T cells to learn direct molecular network to control metabolism. We found that IL-2-STAT5 axis directly control energy production and amino acid synthesis by targeting essential, rate-limiting enzymes and transporters. STAT5 cooperates with MYC genome-wide to transcriptionally programming T cell metabolism, empowering cell growth and proliferation. In contrast, IL-27 is an immunosuppressive regulatory cytokine, and our work unveiled a cholesterol metabolizing enzyme, Ch25h, as a critical metabolic switch induced by IL-27 and TGFb to constrain T cell mediated skin inflammation. Ch25h generates 25-hydroxychoresterol (25OHC), and 25OHC is secreted into microenvironment and suppress proliferation of bystander T cells, dampening excess inflammation and promote resolution of skin inflammation. We further extended our study to evaluate metabolism in NK cells, and found that NK cells are uniquely and specifically dependent on glycosphingolipid (GSL) synthesis for development, homeostasis and function (11). A rate-limiting enzyme in GSL synthesis, Ugcg, is regulated by an extended super-enhancer structure in NK cells and juxtaposed by a long non-coding RNA, indicating complex and intricated transcriptional regulation of the locus often represented by lncRNAs (7). Those series of work contributed to expand our view on underpinning metabolic states supporting cell type specific immune response. We also contributed to a collaborative work investigating memory CD8 response. We studied the impact of mutations of phosphoinositide 3 kinase (PI3K) on memory CD8 T cells. Patients with gain-of-function mutations of PI3K mutations suffer from viral infections. Using a mouse model, (Pik3cdE1020K/+ mice), we showed that activated Pik3cdE1020K/+ CD8+ T cells failed to sustain expression of proteins critical for maintenance of long-lived memory cells, including TCF1, and mounted inadequate memory responses in vivo. Previous work from our lab also established modulatory roles of micro RNAs, miR-221 and miR-222, in balancing intestinal Th17 cell response. Using gene deleted mouse models, we showed that miR-221 and miR-222 constrained the magnitude of proinflammatory response as a part of negative feedback circuit. Extending this work in a collaborative project this year, we examined the role of miR-221/222 in B cells. Using deletion and rescue screening of microRNAs in mature activated B cells, we identified miR221/222 as a positive regulator of Ig class switch recombination (CSR). Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1, and the gene deleted mice exhibited defective Ig E production in allergic airway challenge. Interrogation of mir221/222 targets identified Foxp1 and Arid1a as putative direct targets which play key roles in CSR to IgE and IgG1. Another direction we took this year to expand our knowledge is to address the question of 3 dimensional chromatin architecture and how it relates to gene transcription. Using HiC approach, we compared 3D structure of type 2 cytokine loci between innate (ILC2) and adaptive T cells (Th2), and observed signal inducible chromatin remodeling that differs between ILC2 and Th2. We further identified cell type specific- and context specific-regulatory elements embedded across type 2 cytokine loci whose differential usage contributes to distinct 3D formation between innate and adaptive cells. We will extend this approach to address type 1 cytokine loci including Ifng, Ifngas1 and Il22 in the manuscript in preparation. Overall, we continue to pursue multi-omics based approach that allows us mapping transcriptome, epigenome, factor binding and chromatin conformation in immune cells at single cell levels to answer the question of how cytokine signals originating in diverse extracellular milieu shape the scope and degree of immune cell responsesin health and diseases.