Early secretion of IL-12 by mouse dendritic cells (DCs) instructs T cells to make IFN-γ. However, only activated, but not naive T cells are able to license DCs for IL-12 production. We hypothesized ...that it might be due to different levels of CD40L expression on the surface of these cells, as CD40 signals are required for IL-12 production. Using quantitative cell-free systems incorporating CD40L in lipid bilayers combined with total internal reflection fluorescence microscopy and flow cytometry, we show that as low as ∼200 CD40L molecules/μm
in combination with IL-4 is sufficient to induce IL-12 production by DCs. Remarkably, CD40L alone is adequate to induce IL-23 secretion by DCs. Thus, although activated T cells have somewhat higher levels of CD40L, it is the combination of CD40L and the cytokines they secrete that licenses DCs and influences the effector class of the immune response.
Eosinophilic esophagitis (EoE) is a disorder characterized by dysfunction and chronic local inflammation of the esophagus. The incidence and prevalence of EoE are increasing worldwide. The mechanisms ...responsible are poorly understood, and effective treatment options are limited. From the lumen outward, the esophagus comprises stratified squamous epithelium, lamina propria, and muscle. The tissue-specific nature of EoE strongly suggests that structural cells in the esophagus are involved in the EoE diathesis. Epithelial basal cell hyperplasia and dilated intercellular spaces are cardinal features of EoE. Some patients with EoE develop lamina propria fibrosis, strictures, or esophageal muscle dysmotility. Clinical symptoms of EoE are only weakly correlated with peak eosinophil count, implying that other cell types contribute to EoE pathogenesis. Epithelial, endothelial, muscle, and fibroblast cells can each initiate inflammation and repair, regulate tissue resident immune cells, recruit peripheral leukocytes, and tailor adaptive immune cell responses. A better understanding of how structural cells maintain tissue homeostasis, respond to cell-intrinsic and cell-extrinsic stressors, and exacerbate and/or resolve inflammatory responses in the esophagus is needed. This knowledge will facilitate the development of more efficacious treatment strategies for EoE that can restore homeostasis of both hematopoietic and structural elements in the esophagus.
Pharmacological inhibitors that block amyloid precursor protein (APP) cleavage and the formation of senile plaques are under development for the treatment of familial Alzheimer's disease. ...Unfortunately, many inhibitors that block γ-secretase-mediated cleavage of APP also have immunosuppressive side effects. In addition to APP, numerous other proteins undergo γ-secretase-mediated cleavage. In order to develop safer inhibitors, it is necessary to determine which of the γ-secretase substrates contribute to the immunosuppressive effects. Because APP family members are widely expressed and are reported to influence calcium flux, transcription and apoptosis, they could be important for normal lymphocyte maturation. We find that APP and amyloid precursor-like protein 2 are expressed by stromal cells of thymus and lymph nodes, but not by lymphocytes. Although signals provided by thymic stromal cells are critical for normal T cell differentiation, lymphocyte development proceeds unperturbed in mice deficient for these APP family members.
Adaptive immune responses begin when naive CD4+ T cells engage peptide+major histocompatibility complex class II and co-stimulatory molecules on antigen-presenting cells (APCs). Notch signaling can ...influence effector functions in differentiated CD4+ T helper and T regulatory cells. Whether and how ligand-induced Notch signaling influences the initial priming of CD4+ T cells has not been addressed. We have found that Delta Like Ligand 4 (DLL4)-induced Notch signaling potentiates phosphatidylinositol 3-OH kinase (PI3K)-dependent signaling downstream of the T cell receptor+CD28, allowing naive CD4+ T cells to respond to lower doses of antigen. In vitro, DLL4-deficient APCs were less efficient stimulators of CD4+ T cell activation, metabolism, proliferation, and cytokine secretion. With deletion of DLL4 from CD11c+ APCs in vivo, these deficits translated to an impaired ability to mount an effective CD4+-dependent anti-tumor response. These data implicate Notch signaling as an important regulator of adaptive immune responses.
•Notch enhances the magnitude, kinetics, and quality of primary immune responses•Ligand-induced Notch signaling increases the Ag sensitivity of naive CD4+ T cells•In CD4+ T cells, Notch signaling potentiates PI3K signaling downstream of TCR+CD28•DLL4 on APCs is physiologically important for CD4+-mediated T cell responses in vivo
Notch signaling influences effector functions in fully differentiated CD4+ T cells. Laky et al. show that Notch can also enhance T cell activation during the priming phase by increasing the frequency of CD4+ T cells that respond and by improving the quality of the response on a per-cell basis.
It is commonly believed that IL‐12 produced by DCs in response to pathogens is the first signal that stimulates the production of IFN‐γ by NK cells. However, IL‐12 production by DCs in response to ...bacterial LPS depends on either engagement of CD40 by CD40L on activated T cells or IFN‐γ from NK cells. This suggests that during the primary immune response, NK cells produce IFN‐γ before IL‐12 production by DCs. Here, using single‐cell measurements, cell sorting and mouse lines deficient in IL‐12, IL‐23, type I IFN receptor and the IL‐18 receptor, we show that a subset of BM‐derived DCs characterized by low expression of MHC class II (MHCIIlow) stimulates IFN‐γ production by NK cells. The expression of Toll‐like Receptor (TLR) 4 on DCs but not NK cells was required for such NK‐derived IFN‐γ. In addition, soluble factor(s) produced by LPS‐activated MHCIIlow DCs were sufficient to induce IFN‐γ production by NK cells independent of IL‐12, IL‐23, and IL‐18. This response was enhanced in the presence of a low dose of IL‐2. These results delineate a previously unknown pathway of DC‐mediated IFN‐γ production by NK cells, which is independent of commonly known cytokines.
Dendritic cells secret soluble factor(s) that triggers IFN‐γ production by NK cells independent of IL‐12, IL‐23 and IL‐18.
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