Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22.

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.

T cell plasticity in renal autoimmune disease.

The presence of immune cells is a morphological hallmark of rapidly progressive glomerulonephritis, a disease group that includes anti-glomerular basement membrane glomerulonephritis, lupus nephritis, and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The cellular infiltrates include cells from both the innate and the adaptive immune responses. The latter includes CD4+ and CD8+ T cells. In the past, CD4+ T cell subsets were viewed as terminally differentiated lineages with limited flexibility. However, it is now clear that Th17 cells can in fact have a high degree of plasticity and convert, for example, into pro-inflammatory Th1 cells or anti-inflammatory Tr1 cells. Interestingly, Th17 cells in experimental GN display limited spontaneous plasticity. Here we review the literature of CD4+ T cell plasticity focusing on immune-mediated kidney disease. We point out the key findings of the past decade, in particular that targeting pathogenic Th17 cells by anti-CD3 injection can be a tool to modulate the CD4+ T cell response. This anti-CD3 treatment can trigger a regulatory phenotype in Th17 cells and transdifferentiation of Th17 cells into immunosuppressive IL-10-expressing Tr1 cells (Tr1exTh17 cells). Thus, targeting Th17 cell plasticity could be envisaged as a new therapeutic approach in patients with glomerulonephritis.

Publisher Correction: TGF-ß signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

TGF-ß signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer.

IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-ß1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-ß signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-ß1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-ß signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-ß signaling. We show that TGF-ß, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.

Title: IL-10-producing T cells and their dual functions.

Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, which significantly contributes to the maintenance and reestablishment of immune homeostasis. However, this classical view fails to fully describe the pleiotropic roles of IL-10. Indeed, IL-10 can also promote immune responses, e.g. by supporting B-cell and CD8+ T-cell activation. The reasons for these seemingly opposing functions are unclear to a large extent. Recent and previous studies suggest that the cellular source and the microenvironment impact the function of IL-10. However, studies addressing the mechanisms which determine whether IL-10 promotes inflammation or controls it have just begun. This review first summarizes the recent findings on the heterogeneity of IL-10 producing T cells and their impact on the target cells. Finally, we will propose two possible explanations for the dual functions of IL-10.

Molecular and functional heterogeneity of IL-10-producing CD4+ T cells.

IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease demonstrate a deficiency in this specific regulatory T-cell subpopulation.

Role of IL-10 Receptor Signaling in the Function of CD4+ T-Regulatory Type 1 cells: T-Cell Therapy in Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is caused by the interplay of various factors. It occurs in genetically susceptible people due to dysregulated immune responses to several unknown antigens, including those derived from the commensal microbiota. Effector T-helper cells, especially TH17 cells, are considered a major driver of disease progression. The endogenous resident counterparts of effector T-helper cells are the regulatory T cells, mainly Foxp3+ Treg cells and type 1 regulatory (TR1) T cells. Both have strong immune regulatory capacity and can terminate immune responses. Interestingly, the expression of IL-10 receptor on regulatory T cells has a high impact on the regulatory capacity of these cells. Inflammatory bowel disease is becoming a global health issue. No curative therapy is currently available. However, initial clinical trials have been conducted successfully, proving the safety of a regulatory T-cell-based therapy. This therapy might lead to long-lasting remission and to a possible cure for IBD. This review provides a summary of the current findings and the outcome of the clinical trials based on T-cell therapy for IBD and for other inflammatory conditions.