ABSTRACT
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 calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin that dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1-deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1-deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor RORγT (where ROR is RAR-related orphan receptor) as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21, and IL-10. In the murine model of experimental EAE, we found a strong reduction of the disease outcome in conditional NFATc1-deficient mice, as compared with control littermates. This was accompanied by a diminished inflammation in the brain and spinal cord and reduced IL-17A and IFN-γ expression by antigen-specific spleen, spinal cord, and brain cells. Altogether, these results reveal an important role of NFATc1 in inducing Th17-cell responses and IFN-γ, both being relevant for the EAE development.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/prevention & control , NFATC Transcription Factors/deficiency , T-Lymphocytes/immunology , Animals , Cell Differentiation/immunology , Cytokines/metabolism , Down-Regulation , Encephalomyelitis, Autoimmune, Experimental/etiology , Encephalomyelitis, Autoimmune, Experimental/immunology , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Interleukin-10/metabolism , Interleukin-17/genetics , Interleukin-17/metabolism , Interleukins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , NFATC Transcription Factors/genetics , NFATC Transcription Factors/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Interleukin/metabolism , Spleen/immunology , Spleen/pathology , T-Lymphocytes/pathology , Th1 Cells/immunology , Th1 Cells/pathology , Th17 Cells/immunology , Th17 Cells/pathology , Transforming Growth Factor beta1/metabolismABSTRACT
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.
Subject(s)
Adenocarcinoma/immunology , Basic-Leucine Zipper Transcription Factors/immunology , Carcinoma, Squamous Cell/immunology , Lung Neoplasms/immunology , Neoplasm Proteins/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/immunology , Receptors, Interleukin-6/immunology , STAT3 Transcription Factor/immunology , Th17 Cells/immunology , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Animals , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/immunology , Humans , Lung Neoplasms/pathology , Male , Mice , Middle Aged , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathologyABSTRACT
IL-6 plays a central role in supporting pathological T(H2) and T(H17) cell development and inhibiting the protective T regulatory cells in allergic asthma. T(H17) cells have been demonstrated to regulate allergic asthma in general and T-bet-deficiency-induced asthma in particular. Here we found an inverse correlation between T-bet and Il-6 mRNA expression in asthmatic children. Moreover, experimental subcutaneous immunotherapy (SIT) in T-bet((-/-)) mice inhibited IL-6, IL-21R and lung T(H17) cells in a setting of asthma. Finally, local delivery of an anti-IL-6R antibody in T-bet((-/-)) mice resulted in the resolution of this allergic trait. Noteworthy, BATF, crucial for the immunoglobulin-class-switch and T(H2),T(H17) development, was found down-regulated in the lungs of T-bet((-/-)) mice after SIT and after treatment with anti-IL-6R antibody, indicating a critical role of IL-6 in controlling BATF/IRF4 integrated functions in T(H2), T(H17) cells and B cells also in a T-bet independent fashion in allergic asthma.
Subject(s)
Basic-Leucine Zipper Transcription Factors/immunology , Interferon Regulatory Factors/immunology , Interleukin-6/immunology , T-Box Domain Proteins/immunology , Th17 Cells/immunology , Th2 Cells/immunology , Transcription Factors/immunology , Animals , Antibodies/metabolism , Asthma/genetics , Asthma/immunology , Asthma/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Basic-Leucine Zipper Transcription Factors/metabolism , Child , Child, Preschool , Female , Humans , Hypersensitivity/genetics , Hypersensitivity/immunology , Hypersensitivity/metabolism , Immunotherapy/methods , Interferon Regulatory Factors/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lung/immunology , Lung/metabolism , Male , Mice , RNA, Messenger/genetics , RNA, Messenger/immunology , Receptors, Interleukin-21/genetics , Receptors, Interleukin-21/immunology , Receptors, Interleukin-21/metabolism , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/immunology , Receptors, Interleukin-6/metabolism , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Th17 Cells/metabolism , Th2 Cells/metabolism , Transcription Factors/metabolismABSTRACT
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.
