Type I IFNs Regulate Effector and Regulatory T Cell Accumulation and Anti-Inflammatory Cytokine Production during T Cell–Mediated Colitis

Abstract

We explored the function of endogenous type I interferons (IFN-1) in the colon using the T cell adoptive transfer model of colitis. Colon mononuclear phagocytes (MP) constitutively produced IFN-1 in a TRIF-dependent manner. Transfer of CD4+CD45RBhi T cells from wild type (WT) or interferon α/β receptor subunit 1 knockout (IFNAR1−/−) mice into RAG−/− hosts resulted in similar onset and severity of colitis. In contrast, RAG−/− x IFNAR1−/− double knockout (DKO) mice developed accelerated severe colitis compared to RAG−/− hosts when transferred WT CD4+CD45RBhi T cells. IFNAR signaling on host hematopoietic cells was required to delay colitis development. MPs isolated from the colon lamina propria of IFNAR1−/− mice produced less IL-10, IL-1 receptor antagonist (IL-1RA) and IL-27 compared to WT MPs. Accelerated colitis development in DKO mice was characterized by early T cell proliferation and accumulation of CD11b+CD103− dendritic cells in the mesenteric lymph nodes, both of which could be reversed by systemic administration of IL-1RA (anakinra). Co-transfer of CD4+CD25+ regulatory T cells (Tregs) from WT or IFNAR1−/− mice prevented disease caused by CD4+CD45RBhi T cells. However, WT CD4+CD25+Foxp3GFP+ Tregs co-transferred with CD4+CD45RBhi T cells into DKO hosts failed to expand or maintain Foxp3 expression and gained effector functions in the colon. These data are the first to demonstrate an essential role for IFN-1 in the production of anti-inflammatory cytokines by gut MPs and the indirect maintenance of intestinal T cell homeostasis by both limiting effector T cell expansion and promoting Treg stability.

Type I Interferons Control Proliferation and Function of the Intestinal Epithelium

“…Furthermore, our data suggest that the role of CK1␣ in regulating intestinal homeostasis is at least in part mediated by its effects on the stability and levels of IFNAR1 and the ensuing alterations in IFN signaling. Although microbiota-supported constitutive tonic IFN signaling has been described in the gut (11,12), the role of this signaling in regulating gut renewal and function was a challenge to evaluate due to the potential phenotypic similarity of mice lacking the Ifnar1 gene and wild-type mice exhibiting rapid IFNAR1 degradation under inflammatory conditions (28). The concurrent stabilization of IFNAR1 and ␤-catenin upon CK1␣ inactivation enabled us to determine that IFN plays an important role in restricting the proliferation and viability of the intestinal epithelium (Fig.…”

“…Among these cytokines are type I interferons (IFN) that activate a cognate cell surface receptor (consisting of the IFNAR1 and IFNAR2 chains) and signal to induce the transcription of IFN-stimulated genes (ISGs), some of which are known for their antiproliferative properties (10). Despite the known suppressive effects of IFN on cell proliferation and constitutive induction of IFN in the gut (11,12), the role of these cytokines in regulating intestinal epithelium proliferation and function remains poorly understood.…”

Modulators affecting the immune dialogue between human immune and colon cancer cells

“…According to van Dooren et al [20] there is a difference between cytokine production by whole blood with CCL11, IL-23 and IL-12p40 solely presented, and lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMC) producing IL-20, vascular endothelial growth factor (VEGF) and GM-colony stimulating factor (CSF). Endogenous type interferon 1 (IFN-1) released by colon mononuclear cells in mice with T-cell colitis has been demonstrated to be essential for stimulated production of the anti-inflammatory cytokines IL-10, IL-1ra and IL-27 [21] . Inflammasomes are closely related to chronic inflammation since they act as activators of IL-1β and IL-18 release by PBMC [22,23] .…”

Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue

“…IFN-␥, produced by T cells and natural killer cells, is critical for protection of mice from C. burnetii infection and eventual clearance of the bacteria (18)(19)(20)(21). A primary downstream effect of type I IFN signaling production is increased expression of IL-10, resulting in dampened responses and cytokine expression (22). Type I IFN can also dampen inflammasome signaling (23), and this is a primary mechanism by which type I IFN promotes infection with M. tuberculosis (2,24).…”