IL-15-dependent balance between Foxp3 and RORγt expression impacts inflammatory bowel disease

Abstract

The ability of CD4+ T cells to change their phenotype and to specialize into different functional subsets may enhance the risk of autoimmune diseases. Here we investigate how a pleiotropic cytokine interleukin (IL)-15 may modify the functional commitment of CD4+ T cells expressing the lineage-associated transcription factors: forkhead box P3 (Foxp3; Treg) and RORγt (Th17) in the context of inflammatory bowel disease (IBD). We demonstrate in mice that impaired delivery of IL-15 to CD4+ T cells in the colon downmodulates Foxp3 expression (diminishing STAT5 phosphorylation) and enhances RORγt expression (by upregulating the expression of Runx1). In consequence, CD4+ T cells deprived of IL-15 rapidly trigger IBD characterized by enhanced production of pro-inflammatory cytokines (interferon-γ, IL-6) and accumulation of Th1/Th17 cells. Overall, our findings indicate a potentially beneficial role of IL-15 in IBD by fine-tuning the balance between Treg and Th17 cells and controlling intestinal inflammation.

CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented in trans

“…1D). Thus, contrary to previous reports [12, 26], our results indicate that IL-15 expression is not a feature associated with CD4 T cells, and therefore argue against an autocrine role for IL-15 in CD4 T cells.…”

“…Surprisingly, and in contrast to previous studies [12, 26], Il15 gene reporter mice analysis and quantitative real-time RT-PCR results failed to provide evidence for IL-15 expression in CD4 T cells. Moreover, CD4 T cells did not express IL-15Rα, which is the high-affinity receptor required for IL-15 trans -presentation to IL-2Rβ/γc expressing target cells [27, 28], and which is required for optimal IL-15 signaling in cis [20, 29, 30].…”

“…IL-2 signaling downregulates IL-17 expression [23], and IL-15 reportedly acts the same way on Th17 cells [12, 26]. If there would be autocrine effects of IL-15, we expected to see increased IL-17 expression in Il15 −/− CD4 T cells.…”

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

“…The last factor for the pathogenesis and progression of IBD that deserves to be mentioned here is the adaptive immune response. It is generally acknowledged that increased pro-inflammatory cytokines produced by the T-helper cells or decreased anti-inflammatory cytokines induced by ineffective regulatory T-cells contribute to the pathogenesis of IBD (23, 24). Nevertheless, since the pathogenesis of IBD is complex and the exact underlying mechanisms still remain unclear, no effective therapeutic strategies have been developed for the treatment of IBD.…”

CD25 signaling regulates the function and stability of peripheral Foxp3+ regulatory T cells derived from the spleen and lymph nodes of mice

“…Tregs can be divided into nature Tregs (nTregs) and induced Tregs (iTregs), both of which have been shown to play key roles in a variety of immune diseases including hepatic ischemia-reperfusion injury (IRI), acute hepatic damage, acute graft-versus-host disease, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), rheumatoid arthritis, and chronic obstructive pulmonary disease (Tosiek et al, 2016;Miyara et al, 2014;Okamura et al, 2015;Salter, 1989). However, the stability of Tregs has long been controversial; some evidence demonstrates that Tregs may be unstable and dysfunctional, especially in an inflammatory environment, in which Tregs can readily transform into T-helper (Th) cells such as Th1, Th2, Th17, and Tfh cells and accelerate inflammatory reactions, thereby exacerbating the underlying disease (Feuerer et al, 2009;Wan and Flavell, 2007;Lu et al, 2010).…”