Cytokine signaling, immunoregulation and autoimmune disease

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

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. This year we made several advances in understanding the regulation of cytokine production in innate lymphoid cells, focusing on natural killer (NK) cells. Our previous work established that In NK cells and other innate lymphoid cells acquire competent enhancers during lineage development, and formation of de novo enhancers is a mechanism underlying innate memory in activated NK cells and macrophages. In work this year, we investigated how primed and de novo enhancers coordinate to facilitate high-magnitude gene induction during acute activation. Epigenomic and transcriptomic analyses of regions near highly induced genes (HIGs) in NK cells both in vitro and in a model of Toxoplasma gondii infection revealed de novo chromatin accessibility and enhancer remodeling controlled by STATs. Acute NK cell activation redeployed the lineage-determining transcription factor T-bet to de novo enhancers, independent of DNA-sequence-specific motif recognition. Thus, acute stimulation reshapes enhancer function through the combinatorial usage and repurposing of both lineage-determining and signal-regulated transcription factors to ensure an effective response. Previous work from our lab also established that STAT5 is essential for NK cell development. In a collaborative project, we investigated the roles of STAT5 and its upstream cytokines interleukin-2 (IL-2) and IL-15 during viral infection. We found that STAT5 is induced in NK cells by IL-12 and STAT4 early after infection and that partial STAT5 deficiency results in a defective capacity of NK cells to generate long-lived memory cells. Furthermore, we identified a functional dichotomy in IL-2 and IL-15 responses during viral infection; that is, both cytokines drive clonal expansion, but only IL-15 is required for memory NK cell survival. Extending our studies of T cell memory, we generated single-cell transcriptomes and epigenetic profiles of CD8 T cells responding to acute and chronic viral infections and identified an important factor that regulates memory. During chronic viral infection and cancer, a self-renewing stem-like CD8+ T cell subset maintains long-term immunity, essential for the effectiveness of immunotherapy and this year we identified a role for BACH2 in these stem-like cells. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8+ T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8+ T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. This work reveals a new mechanism that enforces commitment to stem-like CD8+ lineage and prevents an alternative terminally exhausted cell fate. CD4 helper T (Th) cells have the capacity to acquire multiple fates to combat diverse types of microbial pathogens. We investigated the role of microRNAs in this process and identified miR-221 and miR-222 as factors that modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-. Molecular targets of miR-221 and miR-222 included Maf and Il23r, and loss of miR-221 and miR-222 expression shifted the transcriptomic spectrum of intestinal Th17 cells to a proinflammatory signature. Th17 cells lacking miR-221 and miR-222 expanded more efficiently in response to IL-23 and both global and T cell-specific deletion of miR-221 and miR-222 rendered mice prone to mucosal barrier damage. This work demonstrates that miR-221 and miR-222 are an integral part of intestinal Th17 cell responses and constrain the magnitude of proinflammatory response. Other ongoing work this year examines the role of miR-221/222 in B cells. Helper T cells also control immune responses with Foxp3-expressing being a critical element in constraining inflammation. In work this year, a murine asthma model of steroid-resistant airway inflammation was used to show that combining systemic steroids and intranasal IL-27 reversed the inflammation and Foxp3+ regulatory T cells (Tregs) were a critical subset in this response. Specifically, IL-27 enhanced expression of the glucocorticoid receptor- isoform in Tregs, whereas overexpression of an inhibitory glucocorticoid receptor in Tregs alone was sufficient to elicit steroid resistance. This work reveals an unexpected role of Tregs in controlling inflammation and asthma. Another subset of helper T cells is follicular helper T cells, which promote the differentiation of B cells in germinal centers (GCs). In collaborative work this year, we found that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell-derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh-B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma.