Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways

Baer, Alan; Colon-Moran, Winston; Bhattarai, Nirjal

doi:10.1038/s41598-018-29355-0

Title: Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways

Journal Article · Thu Jul 19 00:00:00 EDT 2018 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-018-29355-0· OSTI ID:1624410

Baer, Alan ^[1]; Colon-Moran, Winston ^[1]; Bhattarai, Nirjal ^[1]

U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Biologics Evaluation and Research. Division of Cellular and Gene Therapies

Immune responses against gene therapy products limit its therapeutic efcacy and present a safety risk. Identification of agents that blunt immune reactions may aid in developing novel immunomodulatory therapies. Fingolimod (FTY720) is an FDA approved immunomodulatory drug for treating multiple sclerosis that inhibits lymphocyte egress from lymphoid tissues by down regulating sphingosine-1 phosphate receptor (S1PR). Recent studies found that FTY720 inhibits T cell activation (TCA) in a S1PRindependent manner; however, the mechanism is incompletely understood. Here we characterized the effects of FTY720 on human T cell receptor (TCR) signaling pathways. FTY720 inhibited both the TCR-dependent and independent activation of primary human T cells. FTY720 did not affect proximal TCR signaling events as measured by phosphorylation of Lck, ZAP-70 and LAT; however, inhibited PMA/Ionomycin induced distal TCR signaling as measured by IL-2, IFN-γ release and CD25 expression. FTY720 induced aberrant NFAT1, AP1 and NFκB activation which were associated with increased acetylation of histone (H3K9). Phosphorylated FTY720 did not inhibit TCA, and arachidonic acid did not rescue FTY720 mediated inhibition of TCA. These data suggest that FTY720 mediated inhibition of TCA is due to inhibition of distal TCR signaling. Understanding FTY720-mediated inhibition of TCA may aid in developing novel FTY720-based immunomodulatory agents.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 1624410

Journal Information:: Scientific Reports, Vol. 8, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (29)

Anti-inflammatory Agents: Present and Future Dinarello, Charles A. Cell, Vol. 140, Issue 6 https://doi.org/10.1016/j.cell.2010.02.043	journal	March 2010
Molecular Basis of NF-κB Signaling Napetschnig, Johanna; Wu, Hao Annual Review of Biophysics, Vol. 42, Issue 1 https://doi.org/10.1146/annurev-biophys-083012-130338	journal	May 2013
Genetically modified T cells in cancer therapy: opportunities and challenges Sharpe, M.; Mount, N. Disease Models & Mechanisms, Vol. 8, Issue 4 https://doi.org/10.1242/dmm.018036	journal	April 2015
NFAT proteins: key regulators of T-cell development and function Macian, Fernando Nature Reviews Immunology, Vol. 5, Issue 6 https://doi.org/10.1038/nri1632	journal	June 2005
Insights into the initiation of TCR signaling Chakraborty, Arup K.; Weiss, Arthur Nature Immunology, Vol. 15, Issue 9 https://doi.org/10.1038/ni.2940	journal	August 2014
Toxicities of chimeric antigen receptor T cells: recognition and management Brudno, Jennifer N.; Kochenderfer, James N. Blood, Vol. 127, Issue 26 https://doi.org/10.1182/blood-2016-04-703751	journal	June 2016
Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation Mazzola, Maria Antonietta; Raheja, Radhika; Murugaiyan, Gopal Journal of Neuroinflammation, Vol. 12, Issue 1 https://doi.org/10.1186/s12974-015-0460-z	journal	December 2015
Src-family kinases negatively regulate NFAT signaling in resting human T cells Baer, Alan; Colon-Moran, Winston; Xiang, Jinhua PLOS ONE, Vol. 12, Issue 10 https://doi.org/10.1371/journal.pone.0187123	journal	October 2017
Lck and the nature of the T cell receptor trigger Davis, Simon J.; van der Merwe, P. Anton Trends in Immunology, Vol. 32, Issue 1 https://doi.org/10.1016/j.it.2010.11.003	journal	January 2011
Discovery of fingolimod, the sphingosine 1-phosphate receptor modulator and its application for the therapy of multiple sclerosis Chiba, Kenji; Adachi, Kunitomo Future Medicinal Chemistry, Vol. 4, Issue 6 https://doi.org/10.4155/fmc.12.25	journal	April 2012
Adaptive and innate immune responses to gene transfer vectors: role of cytokines and chemokines in vector function Chen, D.; Murphy, B.; Sung, R. Gene Therapy, Vol. 10, Issue 11 https://doi.org/10.1038/sj.gt.3302031	journal	May 2003
Anti-Inflammatory Agents for Cancer Therapy Rayburn, Elizabeth Molecular and Cellular Pharmacology, Vol. 1, Issue 1 https://doi.org/10.4255/mcpharmacol.09.05	journal	February 2009
Progress and prospects: immune responses to viral vectors Nayak, S.; Herzog, R. W. Gene Therapy, Vol. 17, Issue 3 https://doi.org/10.1038/gt.2009.148	journal	November 2009
Prostaglandin E ₂ and T cells: friends or foes? Sreeramkumar, Vinatha; Fresno, Manuel; Cuesta, Natalia Immunology & Cell Biology, Vol. 90, Issue 6 https://doi.org/10.1038/icb.2011.75	journal	September 2011
FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors Chiba, Kenji Pharmacology & Therapeutics, Vol. 108, Issue 3 https://doi.org/10.1016/j.pharmthera.2005.05.002	journal	December 2005
The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors Payne, Shawn G.; Oskeritzian, Carole A.; Griffiths, Rachael Blood, Vol. 109, Issue 3 https://doi.org/10.1182/blood-2006-03-011437	journal	September 2006
Phospholipase A2 Murakami, M.; Kudo, I. Journal of Biochemistry, Vol. 131, Issue 3 https://doi.org/10.1093/oxfordjournals.jbchem.a003101	journal	March 2002
Molecular mechanisms of T cell co-stimulation and co-inhibition Chen, Lieping; Flies, Dallas B. Nature Reviews Immunology, Vol. 13, Issue 4 https://doi.org/10.1038/nri3405	journal	March 2013
T cell receptor signalling networks: branched, diversified and bounded Brownlie, Rebecca J.; Zamoyska, Rose Nature Reviews Immunology, Vol. 13, Issue 4 https://doi.org/10.1038/nri3403	journal	March 2013
Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos Liu, Xiaoyu; Wang, Chenfei; Liu, Wenqiang Nature, Vol. 537, Issue 7621 https://doi.org/10.1038/nature19362	journal	September 2016
H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells Karmodiya, Krishanpal; Krebs, Arnaud R.; Oulad-Abdelghani, Mustapha BMC Genomics, Vol. 13, Issue 1 https://doi.org/10.1186/1471-2164-13-424	journal	January 2012
NFAT, immunity and cancer: a transcription factor comes of age Müller, Martin R.; Rao, Anjana Nature Reviews Immunology, Vol. 10, Issue 9 https://doi.org/10.1038/nri2818	journal	August 2010
FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway Ntranos, Achilles; Hall, Olivia; Robinson, Dionne P. Journal of Neuroimmunology, Vol. 270, Issue 1-2 https://doi.org/10.1016/j.jneuroim.2014.03.007	journal	May 2014
T Cell Activation Smith-Garvin, Jennifer E.; Koretzky, Gary A.; Jordan, Martha S. Annual Review of Immunology, Vol. 27, Issue 1 https://doi.org/10.1146/annurev.immunol.021908.132706	journal	April 2009
Distinct TCR signaling pathways drive proliferation and cytokine production in T cells Guy, Clifford S.; Vignali, Kate M.; Temirov, Jamshid Nature Immunology, Vol. 14, Issue 3 https://doi.org/10.1038/ni.2538	journal	February 2013
Association between serum interleukin-6 and frailty in older men: cross-sectional data Tembo, Monica C.; Holloway-Kew, Kara L.; Bortolasci, Chiara C. European Geriatric Medicine, Vol. 12, Issue 4 https://doi.org/10.1007/s41999-021-00490-8	journal	March 2021
T-cell activation Izquierdo, Manuel; Cantrell, Doreen A. Trends in Cell Biology, Vol. 2, Issue 9 https://doi.org/10.1016/0962-8924(92)90199-w	journal	September 1992
AP-1 function and regulation Karin, Michael; Liu, Zheng-gang; Zandi, Ebrahim Current Opinion in Cell Biology, Vol. 9, Issue 2 https://doi.org/10.1016/s0955-0674(97)80068-3	journal	April 1997
Calcineurin-NFATc Regulates Type 2 Inositol 1,4,5-Trisphosphate Receptor (InsP ₃ R2) Expression during Cardiac Remodeling Sankar, Natesan; deTombe, Pieter P.; Mignery, Gregory A. Journal of Biological Chemistry, Vol. 289, Issue 9 https://doi.org/10.1074/jbc.m113.495242	journal	January 2014

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