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Gasdermins (GSDMs) share a common functional domain structure and are best known for their capacity to form membrane pores. These pores are hallmarks of a specific form of cell death called pyroptosis and mediate the secretion of pro-inflammatory cytokines such as interleukin 1β (IL1β) and interleukin 18 (IL18). Thereby, Gasdermins have been implicated in various immune responses against cancer and infectious diseases such as acuteSalmonellaTyphimurium (S.Tm) gut infection. However, to date, we lack a comprehensive functional assessment of the different Gasdermins (GSDMA-E) duringS.Tm infectionin vivo. Here, we have performed littermate-controlled oralS.Tm infections to investigate the impact of all murine Gasdermins. While GSDMA, -C and -E appear dispensable, we show that GSDMD (i) restrictsS.Tm loads in the gut tissue and systemic organs, (ii) controls gut inflammation kinetics, and (iii) prevents epithelium disruption by 72h of the infection. Full protection requires GSDMD expression by both bone-marrow-derived lamina propria cells and intestinal epithelial cells (IECs).In vivoexperiments, 3D- and 2D-enteroid infections further show that infected IEC extrusion proceeds also without GSDMD, but that GSDMD controls the permeabilization and morphology of the extruding cells and affects extrusion kinetics. As such, this work identifies a non-redundant multipronged role of GSDMD in mucosal tissue defence against a common enteric pathogen.HIGHLIGHTSGasdermin D restrictsSalmonellaTyphimurium (S.Tm) translocation across the gut tissue, controls gut inflammation kinetics, and prevents epithelium disruption by 72h of the infection.Gasdermins A, C and E appear dispensable for protection against acuteS.Tm gut infection.Gasdermin D in bone-marrow-derived lamina propria cells and intestinal epithelial cells complement each other to suppress gut tissueS.Tm loads.Gasdermin D is not required for extrusion of infected intestinal epithelial cells but drives their permeabilization and affects qualitative features of the extrusion process.

Hausmann et al. describe a sentinel intercrypt macrophage population in the intestine, which detects Gram-negative microbes breaching the epithelial barrier and elicits epithelial NF-κB signaling in neighboring crypts. The tunability of this crypt-scale response allows the induction of appropriately scaled defenses according to the localization and intensity of microbial triggers., Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage–TNF–IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers., Graphical Abstract

Cancer immunology research is largely focused on the role of cytotoxic immune responses against advanced cancers. Herein, we demonstrate that CD4+ T helper (Th2) cells directly block spontaneous breast carcinogenesis by inducing the terminal differentiation of the cancer cells. Th2 cell immunity, stimulated by thymic stromal lymphopoietin, caused the epigenetic reprogramming of the tumor cells, activating mammary gland differentiation and suppressing epithelial–mesenchymal transition. Th2 polarization was required for this tumor antigen–specific immunity, which persisted in the absence of CD8+ T and B cells. Th2 cells directly blocked breast carcinogenesis by secreting IL-3, IL-5, and GM-CSF, which signaled to their common receptor expressed on breast tumor cells. Importantly, Th2 cell immunity permanently reverted high-grade breast tumors into low-grade, fibrocystic-like structures. Our findings reveal a critical role for CD4+ Th2 cells in immunity against breast cancer, which is mediated by terminal differentiation as a distinct effector mechanism for cancer immunoprevention and therapy.

Background and aims Limiting the pro-inflammatory immune response is critical for the treatment of atherosclerosis. Regulatory B cells (Bregs) can modulate the immune response through interleukin-10 (IL-10). Current data regarding Bregs and atherosclerosis is scarce and conflicting. Methods In this study, we investigated the frequency of IL-10+ B cells during the development of atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr−/−) mice and studied the effect of adoptive transfer of IL-10+ B cells on atherosclerosis. Results We found a very strong inverse correlation between atherosclerosis severity and the frequency of IL-10+ B cells. This effect was cholesterol-independent and observed in spleen, draining lymph nodes and peritoneal cavity. To directly assess the effects of IL-10+ B cells on atherosclerosis, we expanded IL-10+ B cells ex vivo with anti-CD40 and selected pure and viable IL-10-secreting B cells and IL-10- B cells and adoptively transferred them to Ldlr−/− mice, respectively. While IL-10- B cells were strongly atherogenic compared to control-treated mice, IL-10+ B cells did not affect lesion size. Adoptive transfer of IL-10+ B cells strongly reduced circulating leukocyte numbers and inflammatory monocytes. In addition, they decreased CD4+ T cell activation and increased IL-10+ CD4+ T cell numbers. Interestingly, both IL-10+ and IL-10- B cells exacerbated serum cholesterol levels and resulted in fatty livers, which potentially masked the beneficial effects of IL-10+ B cells on atherosclerosis. Conclusions These findings underscore the strong immune-regulating function of IL-10+ B cells and provide additional incentives to explore effective strategies that expand IL-10+ B cells in atherosclerosis.

Novel approaches in cancer immunotherapy have led to effective therapeutics against late-stage cancers. However, the role of the immune system in protection against early-stage cancers remains uncertain. We have previously discovered that thymic stromal lymphopoietin (TSLP) blocks early stages of breast cancer development through activation of CD4+ T cells. TSLP is an epithelium-derived danger signal that plays a key role in initiating an immune response upon cell damage and stress. The aim of this study is to investigate the potential involvement of other epithelial-derived cytokines in the activation of an immune response against premalignant breast lesions. To identify these signals, we analyzed the expression of a wide range of epithelium-derived cytokines in normal mammary glands, premalignant lesions, and late-stage tumors of MMTV-PyMT (PyMTtg) and K14-Cre, Brca1f/f, p53f/f mouse models. These mice spontaneously develop breast tumors that resemble human luminal and basal-like breast cancers, respectively. Of the cytokines examined, IL-1a was highly expressed in premalignant lesions compared to mammary glands and tumors. Additionally, IL-12p40 was upregulated in both early and late stages of breast cancer compared to normal mammary gland. Other cytokines, like IL-7, IL-11, and IL-24, were highly expressed in the mammary gland, but their expression was lost during breast tumorigenesis. In conclusion, we identified upregulation of IL-1a and IL-12p40 in early-stage breast cancer, suggesting a role for these cytokines in inducing antitumor immunity in the breast. Furthermore, we demonstrate selection against expression of IL-7, IL-11, and IL-24 during the process of cancer initiation and promotion, suggesting a role in normal mammary gland homeostasis and possibly immunity against breast carcinogenesis. Taken together, we have identified potential novel therapeutic targets that can be leveraged for breast cancer immunoprevention. Citation Format: Sanne Kroon, Kaitlin Dempsey, Margherita Boieri, Shawn Demehri. Epithelium-derived cytokines in breast carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B102.

Limiting the pro-inflammatory immune response is critical for the treatment of atherosclerosis. Regulatory B cells (Bregs) can modulate the immune response through interleukin-10 (IL-10). Current data regarding Bregs and atherosclerosis is scarce and conflicting.In this study, we investigated the frequency of IL-10We found a very strong inverse correlation between atherosclerosis severity and the frequency of IL-10These findings underscore the strong immune-regulating function of IL-10