Lung cancer is the leading cause of cancer deaths worldwide. The cytokine interleukin-17A supports tumour vascularization and growth, however, its role in lung cancer is unknown. Here we show, in the lungs of patients with lung adenocarcinoma, an increase in interleukin-17A that is inversely correlated with the expression of T-bet and correlated with the T regulatory cell transcription factor Foxp3. Local targeting of interleukin-17A in experimental lung adenocarcinoma results in a reduction in tumour load, local expansion of interferon-γ-producing CD4 + T cells and a reduction in lung CD4 + CD25 + Foxp3 + regulatory T cells. T-bet ( − / − ) mice have a significantly higher tumour load compared with wild-type mice. This is associated with the local upregulation of interleukin-23 and induction of interleukin-17A/interleukin-17R-expressing T cells infiltrating the tumour. Local anti-interleukin-17A antibody treatment partially improves the survival of T-bet ( − / − ) mice. These results suggest that local anti-interleukin-17A antibody therapy could be considered for the treatment of lung tumours.

NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic Keywords: CD4+ T cells r EAE r NFAT r RORγT r Th17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNuclear factor of activated T cells (NFAT) was originally described as a transcription factor inducing the expression of interleukin 2 (IL-2) [1]. The NFAT family of transcription factors consists of five members, named NFAT1-5, and the main forms expressed in T cells are NFATc1 and NFATc2 [2]. NFATc2 is constitutively expressed in T cells [3], whereas NFATc1 is activated upon T-cell receptor stimulation [4]. NFATc1 is the only NFAT protein Correspondence: Prof. Susetta Finotto e-mail: susetta.finotto@uk-erlangen.de family member which acts in a positive autoregulatory loop [5] and thereby augments NFATc1 expression. NFAT proteins reside phosphorylated in the cytoplasm. Upon T-cell receptor activation the phospholipase C signaling pathway is activated, which leads to an induced influx of calcium into the cell. Intracytoplasmatic calcium signaling activates calmodulin, a calcium sensor protein that activates the phosphatase calcineurin. These phosphatase dephosphorylates NFAT proteins, so that they can shuttle into the nucleus where they act as transcription factors on the promoter of target * These authors contributed equally to this work. www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution-NonCommercialNoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Eur. J. Immunol. 2015Immunol. . 45: 1426Immunol. -1440 Immunomodulation 1427 genes such as . Previous studies showed that NFAT proteins play regulatory roles during T-cell differentiation and effector functions. NFATc2 deficiency in T cells diminished Th1 differentiation and induced IL-4 production [7,8]. NFATc2 was also shown to contribute to IL-21 expression and to limit the immunosuppressive function of CD4 + CD25 + Foxp3 + GITR + T regulatory (Treg) cells [8,9]. The role of NFATc1 in T-cell differentiation processes is not fully understood, partially because NFATc1 total knockout mice die at the embryonic stage [10]. Previous analysis on Th1-and Th2-skewed T cells isolated from NFATc1−/− /Rag1 −/− chimeric mice revealed an involvement of NFATc1 in the induction of the Th2-cytokines IL-4 and IL-6, whereas it had no effect on interferon gamma (IFN-γ) and IL-2 expression in Th1 cells [11,12]. Other studies showed that NFATc1 induces IL-4 expression. In Th17 cells, NFAT transcription factors have been shown to be involved in the gene expression of RORγT (where ROR is RARrelated orphan receptor), . This has been shown mostly for other NFAT transcription factor family members than NFATc1. EAE is the murine model for the early in...

SummaryBackground NFATc1 isoforms are highly regulated in peripheral T cells where they contribute to the effector function and cell homeostasis. Objective Here, we investigated the role of NFATc1 in asthma and in T cells.Methods In a murine model of allergic asthma, we analysed differences in T-cell development in this allergic disease model, between wild-type and NFATc1 conditional knockout mice. Thus, we performed quantitative real-time PCR to investigate the mRNA expression of Th2-associated genes as well as genes that are involved in IgE immunoglobulin class-switch. Additionally, we used ELISA, Western blot and flow cytometry (FACS) to analyse protein concentrations of Th1-, Th2-and Th17-specific transcription factors and cytokines and the Th2 chemokine, thymus and activation-regulated chemokine/ chemokine ligand 17 (TARC/CCL17) by ELISA. Results Mice lacking NFATc1 in CD4+ T cells display a significant reduction in lung Th2 and Th17 as well as an increase of Th1 cells in an experimental asthma model. Additionally, Batf gene, a recently described transcription factor of the Th2 and Th17 cell differentiation as well as a key T and B transcription factor involved in the IgE immunoglobulin class-switch, was found decreased in the lungs of these mice. As a consequence, serum OVA-specific IgE and IgG1 levels were found significantly decreased after allergen exposure and in the absence of NFATc1 in T cells in experimental allergic asthma. Conclusions and Clinical Relevance Targeting NFATc1 in T lymphocytes ameliorated the allergic trait in the airways of NFATc1 fl/fl xCD4Cre mice. NFATc1 emerges as a novel target for anti-allergy intervention.

In a recent study we reported increased expression of IL-17A in the lung of patients with lung adenocarcinoma. Local blockade of IL-17A in the lung, in a model of lung cancer revealed enhanced anti-tumor immunity characterized by increased IFNγ, a diminished T-regulatory cell number and reduced tumor growth.

Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (RORγT), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.