TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8(+)CD103(+) DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity

Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis

Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti-PD-1 immunotherapy. The mechanism of liver metastases-induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (Tregs) and modulation of intratumoral CD11b+ monocytes. The dysfunctional immune state could not be reversed by anti-PD-1 monotherapy unless Treg cells were depleted (anti-CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding Treg and CD11b+ monocyte targeting agents in combination with anti-PD-1 to treat patients with cancer with liver metastasis

CD4 T cells isolated from IL-1R1^ΔT mice display non-impaired differentiation <i>in vitro</i>.

<p><i>In vitro</i> polarization assay of MACS-purified CD4 T cells activated under Th0, Th17 and Th1 conditions (described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161505#sec002" target="_blank">materials and methods</a> section) for 4 days. Data are shown as representative FACS plots gated on VD^-/CD4⁺ cells with average frequencies per group and as mean +SEM of n = 3 of each genotype. Experiments were performed twice with similar results.</p

Oral epithelial cells orchestrate innate Type 17 responses to Candida albicans through the virulence factor Candidalysin

Candidalysin, a hypha-associated fungal peptide, drives interleukin-17 responses to Candida albicans . </jats:p

Cutting Edge: IL-6-Driven Immune Dysregulation Is Strictly Dependent on IL-6R alpha-Chain Expression

IL-6 binds to the IL-6R alpha-chain (IL-6R alpha) and signals via the signal transducer gp130. Recently, IL-6 was found to also bind to the cell surface glycoprotein CD5, which would then engage gp130 in the absence of IL-6R alpha. However, the biological relevance of this alternative pathway is under debate. In this study, we developed a mouse model, in which murine IL-6 is overexpressed in a CD11c-Cre-dependent manner. Transgenic mice developed a lethal immune dysregulation syndrome with increased numbers of Ly-6G(+) neutrophils and Ly-6C(hi) monocytes/macrophages. IL-6 overexpression promoted activation of CD4(+) T cells while suppressing CD5(+) B-1a cell development. However, additional ablation of IL-6R alpha protected IL-6-overexpressing mice from IL-6-triggered inflammation and fully phenocopied IL-6R alpha-deficient mice without IL-6 overexpression. Mechanistically, IL-6R alpha deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6R alpha is the only biologically relevant receptor for IL-6 in mice

IL-1 signaling is critical for expansion but not generation of autoreactive GM-CSF+ Th17 cells

Interleukin‐1 (IL‐1) is implicated in numerous pathologies, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the exact mechanism by which IL‐1 is involved in the generation of pathogenic T cells and in disease development remains largely unknown. We found that following EAE induction, pertussis toxin administration leads to IL‐1 receptor type 1 (IL‐1R1)‐dependent IL‐1β expression by myeloid cells in the draining lymph nodes. This myeloid‐derived IL‐1β did not vitally contribute to the generation and plasticity of Th17 cells, but rather promoted the expansion of a GM‐CSF (+) Th17 cell subset, thereby enhancing its encephalitogenic potential. Lack of expansion of GM‐CSF‐producing Th17 cells led to ameliorated disease in mice deficient for IL‐1R1 specifically in T cells. Importantly, pathogenicity of IL‐1R1‐deficient T cells was fully restored by IL‐23 polarization and expansion in vitro. Therefore, our data demonstrate that IL‐1 functions as a mitogenic mediator of encephalitogenic Th17 cells rather than qualitative inducer of their generation