Search

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22–IL-22BP axis in HCC.

© 2021 The Authors., The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers., Hyun-Dong Chang is supported by the Dr. Rolf M. Schwiete Foundation. Susanne Melzer and Attila Tarnok thank De Novo Software for providing FCS Express. Enrico Lugli is supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC IG20676). Gabriele De Simone and Giovanni Galletti were supported by Fellowships from the Fondazione Italiana per la Ricerca sul Cancro-Associazione Italiana per la Ricerca sul Cancro (FIRC-AIRC). Jun Dong is supported by Deutsche Forschungsgemeinschft (DFG, German Research Foundation) Projektnummer 389687267 and Chinesisch-Deutsches Zentrum für Wissenschaftsförderung [Sino-German Center for Research Promotion (SGC)] grant C-0072. Nicola Gagliani, Samuel Huber and Franziska Muscate are supported by DFG fundings: SFB841,GA 2441/3-1, HU 1714/10-1. The tetramer APC-conjugated H-2K (d) HIV-1 gag197-205 AMQMLKETI used in TDS assay for mouse blood T cells was obtained through the NIH Tetramer Facility. Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14-1. Supported by the following grants: AIRC 5X1000 2018 id. 21147 (Lorenzo Moretta); AIRC IG 2017 id. 19920 (Lorenzo Moretta); RC-2020 OPBG (Lorenzo Moretta); AIRC and European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 800924 (Linda Quatrini). Dirk Baumjohann was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Emmy Noether Programme BA 5132/1-2 (252623821) and Germany's Excellence Strategy EXC2151 (390873048).

A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)negα4β7+ precursors in the adult murine bone marrow. Expanded Linnegα4β7+ precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.

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

Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4+ T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell–derived IL-22BP. Lastly, intestinal CD4+ T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor–α (anti–TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22. Our findings suggest that anti–TNF-α therapy may act at least in part by suppressing IL-22BP and point toward a more specific potential therapy for IBD.

Background & Aims Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice. Methods We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf–/–, Lta–/–, and Ltb–/– mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times. Results Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp–/– mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte–derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC. Conclusions Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.

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.

The intestine is colonized by hundreds of different species of commensal bacteria, viruses, and fungi. Therefore, the intestinal immune system is constantly being challenged by foreign antigens. The immune system, the commensal microbiota, and the intestinal epithelial surface have to maintain a tight balance to guarantee defense against potential pathogens and to prevent chronic inflammatory conditions at the same time. Failure of these mechanisms can lead to a vicious cycle in which a perpetual tissue damage/repair process results in a pathological reorganization of the normal mucosal surface. This dysregulation of the intestine is considered to be one of the underlying causes for both inflammatory bowel disease (IBD) and colorectal cancer. TH17 cells have been associated with immune-mediated diseases, such as IBD, since their discovery in 2005. Upon mucosal damage, these cells are induced by a combination of different cytokines, such as IL-6, TGF-β, and IL-1β. TH17 cells are crucial players in the defense against extracellular pathogens and have various mechanisms to fulfill their function. They can activate and attract phagocytic cells. Additionally, TH17 cells can induce the release of anti-microbial peptides from non-immune cells, such as epithelial cells. The flip side of the coin is the strong potential of TH17 cells to be pro-inflammatory and promote pathogenicity. TH17 cells have been linked to both mucosal regeneration and inflammation. In turn, these cells and their cytokines emerged as potential therapeutic targets both for inflammatory diseases and cancer. This review will summarize the current knowledge regarding the TH17 cell-enterocyte crosstalk and give an overview of its clinical implications.

Wound healing is a crucial process which protects our body against permanent damage and invasive infectious agents. Upon tissue damage, inflammation is an early event which is orchestrated by a multitude of innate and adaptive immune cell subsets including TH17 cells. TH17 cells and TH17 cell associated cytokines can impact wound healing positively by clearing pathogens and modulating mucosal surfaces and epithelial cells. Injury of the gut mucosa can cause fast expansion of TH17 cells and their induction from naive T cells through Interleukin (IL)-6, TGF-β, and IL-1β signaling. TH17 cells produce various cytokines, such as tumor necrosis factor (TNF)-α, IL-17, and IL-22, which can promote cell survival and proliferation and thus tissue regeneration in several organs including the skin, the intestine, and the liver. However, TH17 cells are also potentially pathogenic if not tightly controlled. Failure of these control mechanisms can result in chronic inflammatory conditions, such as Inflammatory Bowel Disease (IBD), and can ultimately promote carcinogenesis. Therefore, there are several mechanisms which control TH17 cells. One control mechanism is the regulation of TH17 cells via regulatory T cells and IL-10. This mechanism is especially important in the intestine to terminate immune responses and maintain homeostasis. Furthermore, TH17 cells have the potential to convert from a pro-inflammatory phenotype to an anti-inflammatory phenotype by changing their cytokine profile and acquiring IL-10 production, thereby limiting their own pathological potential. Finally, IL-22, a signature cytokine of TH17 cells, can be controlled by an endogenous soluble inhibitory receptor, Interleukin 22 binding protein (IL-22BP). During tissue injury, the production of IL-22 by TH17 cells is upregulated in order to promote tissue regeneration. To limit the regenerative program, which could promote carcinogenesis, IL-22BP is upregulated during the later phase of regeneration in order to terminate the effects of IL-22. This delicate balance secures the beneficial effects of IL-22 and prevents its potential pathogenicity. An important future goal is to understand the precise mechanisms underlying the regulation of TH17 cells during inflammation, wound healing, and carcinogenesis in order to design targeted therapies for a variety of diseases including infections, cancer, and immune mediated inflammatory disease.

CD4+ type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases. © 2013 Nature America, Inc. All rights reserved

Corrigendum: Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells