The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity

TY - JOUR

T1 - The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity

AU - Furmanski, Anna L

AU - Barbarulo, Alessandro

AU - Solanki, Anisha

AU - Lau, Ching-In

AU - Sahni, Hemant

AU - Saldana, Jose Ignacio

AU - D'Acquisto, Fulvio

AU - Crompton, Tessa

N1 - © 2015. Published by The Company of Biologists Ltd.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation. Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca(2+) flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFκB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity upon TCR ligation. These data are important for understanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli-activating ligands such as TGFβ are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments. © 2015, The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/

AB - Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation. Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca(2+) flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFκB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity upon TCR ligation. These data are important for understanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli-activating ligands such as TGFβ are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments. © 2015, The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/

KW - Animals

KW - Cell Differentiation

KW - Cell Proliferation

KW - Gene Expression Regulation

KW - Hedgehog Proteins

KW - Kruppel-Like Transcription Factors

KW - Lymphocyte Activation

KW - Mice

KW - Mice, Inbred C57BL

KW - NF-kappa B

KW - NFATC Transcription Factors

KW - Receptors, Antigen, T-Cell

KW - Signal Transduction

KW - T-Lymphocytes

KW - Transcription Factor AP-1

KW - Transcriptional Activation

KW - Transcriptome

KW - Transforming Growth Factor beta

KW - Up-Regulation

KW - Zinc Finger Protein Gli2

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1242/jcs.165803

DO - 10.1242/jcs.165803

M3 - Article

C2 - 25908851

SN - 0021-9533

VL - 128

SP - 2085

EP - 2095

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 11

ER -