Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis

Research output: Contribution to journalArticle

Matthew Cummings, Anitha Christy Sigamani Arumanayagam, Picheng Zhao, Sunil Kannanganat, Olaf Stuve, Nitin J. Karandikar, Todd N. Eagar

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where pathology is thought to be regulated by autoreactive T cells of the Th1 and Th17 phenotype. In this study we sought to understand the functions of Presenilin 1 (PSEN1) in regulating T cell effector responses in the experimental autoimmune encephalomyelitis (EAE) murine model of MS. PSEN1 is the catalytic subunit of γ-secretase a multimo-lecular protease that mediates intramembranous proteolysis. γ-secretase is known to regulate several pathways of immune importance. Here we examine the effects of disrupting PSEN1 functions on EAE and T effector differentiation using small molecule inhibitors of γ-secretase (GSI) and T cell-specific conditional knockout mice (PSEN1 cKO). Surprisingly, blocking PSEN1 function by GSI treatment or PSEN1 cKO had little effect on the development or course of MOG35-55-induced EAE. In vivo GSI administration reduced the number of myelin antigen-specific T cells and suppressed Th1 and Th17 differentiation following immunization. In vitro, GSI treatment inhibited Th1 differentiation in neutral but not IL-12 polarizing conditions. Th17 differentiation was also suppressed by the presence of GSI in all conditions and GSI-treated Th17 T cells failed to induce EAE following adoptive transfer. PSEN cKO T cells showed reduced Th1 and Th17 differentiation. We conclude that γ-secretase and PSEN1-dependent signals are involved in T effector responses in vivo and potently regulate T effector differentiation in vitro, however, they are dispensable for EAE.

Original languageEnglish (US)
Article numbere0200752
JournalPLoS ONE
Volume13
Issue number8
DOIs
StatePublished - Aug 1 2018

PMID: 30089166

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Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis. / Cummings, Matthew; Arumanayagam, Anitha Christy Sigamani; Zhao, Picheng; Kannanganat, Sunil; Stuve, Olaf; Karandikar, Nitin J.; Eagar, Todd N.

In: PLoS ONE, Vol. 13, No. 8, e0200752, 01.08.2018.

Research output: Contribution to journalArticle

Harvard

Cummings, M, Arumanayagam, ACS, Zhao, P, Kannanganat, S, Stuve, O, Karandikar, NJ & Eagar, TN 2018, 'Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis' PLoS ONE, vol. 13, no. 8, e0200752. https://doi.org/10.1371/journal.pone.0200752

APA

Cummings, M., Arumanayagam, A. C. S., Zhao, P., Kannanganat, S., Stuve, O., Karandikar, N. J., & Eagar, T. N. (2018). Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis. PLoS ONE, 13(8), [e0200752]. https://doi.org/10.1371/journal.pone.0200752

Vancouver

Cummings M, Arumanayagam ACS, Zhao P, Kannanganat S, Stuve O, Karandikar NJ et al. Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis. PLoS ONE. 2018 Aug 1;13(8). e0200752. https://doi.org/10.1371/journal.pone.0200752

Author

Cummings, Matthew ; Arumanayagam, Anitha Christy Sigamani ; Zhao, Picheng ; Kannanganat, Sunil ; Stuve, Olaf ; Karandikar, Nitin J. ; Eagar, Todd N. / Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis. In: PLoS ONE. 2018 ; Vol. 13, No. 8.

BibTeX

@article{04ae167a13ea439783d9d9dcf555256c,
title = "Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis",
abstract = "Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where pathology is thought to be regulated by autoreactive T cells of the Th1 and Th17 phenotype. In this study we sought to understand the functions of Presenilin 1 (PSEN1) in regulating T cell effector responses in the experimental autoimmune encephalomyelitis (EAE) murine model of MS. PSEN1 is the catalytic subunit of γ-secretase a multimo-lecular protease that mediates intramembranous proteolysis. γ-secretase is known to regulate several pathways of immune importance. Here we examine the effects of disrupting PSEN1 functions on EAE and T effector differentiation using small molecule inhibitors of γ-secretase (GSI) and T cell-specific conditional knockout mice (PSEN1 cKO). Surprisingly, blocking PSEN1 function by GSI treatment or PSEN1 cKO had little effect on the development or course of MOG35-55-induced EAE. In vivo GSI administration reduced the number of myelin antigen-specific T cells and suppressed Th1 and Th17 differentiation following immunization. In vitro, GSI treatment inhibited Th1 differentiation in neutral but not IL-12 polarizing conditions. Th17 differentiation was also suppressed by the presence of GSI in all conditions and GSI-treated Th17 T cells failed to induce EAE following adoptive transfer. PSEN cKO T cells showed reduced Th1 and Th17 differentiation. We conclude that γ-secretase and PSEN1-dependent signals are involved in T effector responses in vivo and potently regulate T effector differentiation in vitro, however, they are dispensable for EAE.",
author = "Matthew Cummings and Arumanayagam, {Anitha Christy Sigamani} and Picheng Zhao and Sunil Kannanganat and Olaf Stuve and Karandikar, {Nitin J.} and Eagar, {Todd N.}",
year = "2018",
month = "8",
day = "1",
doi = "10.1371/journal.pone.0200752",
language = "English (US)",
volume = "13",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

RIS

TY - JOUR

T1 - Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis

AU - Cummings, Matthew

AU - Arumanayagam, Anitha Christy Sigamani

AU - Zhao, Picheng

AU - Kannanganat, Sunil

AU - Stuve, Olaf

AU - Karandikar, Nitin J.

AU - Eagar, Todd N.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where pathology is thought to be regulated by autoreactive T cells of the Th1 and Th17 phenotype. In this study we sought to understand the functions of Presenilin 1 (PSEN1) in regulating T cell effector responses in the experimental autoimmune encephalomyelitis (EAE) murine model of MS. PSEN1 is the catalytic subunit of γ-secretase a multimo-lecular protease that mediates intramembranous proteolysis. γ-secretase is known to regulate several pathways of immune importance. Here we examine the effects of disrupting PSEN1 functions on EAE and T effector differentiation using small molecule inhibitors of γ-secretase (GSI) and T cell-specific conditional knockout mice (PSEN1 cKO). Surprisingly, blocking PSEN1 function by GSI treatment or PSEN1 cKO had little effect on the development or course of MOG35-55-induced EAE. In vivo GSI administration reduced the number of myelin antigen-specific T cells and suppressed Th1 and Th17 differentiation following immunization. In vitro, GSI treatment inhibited Th1 differentiation in neutral but not IL-12 polarizing conditions. Th17 differentiation was also suppressed by the presence of GSI in all conditions and GSI-treated Th17 T cells failed to induce EAE following adoptive transfer. PSEN cKO T cells showed reduced Th1 and Th17 differentiation. We conclude that γ-secretase and PSEN1-dependent signals are involved in T effector responses in vivo and potently regulate T effector differentiation in vitro, however, they are dispensable for EAE.

AB - Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) where pathology is thought to be regulated by autoreactive T cells of the Th1 and Th17 phenotype. In this study we sought to understand the functions of Presenilin 1 (PSEN1) in regulating T cell effector responses in the experimental autoimmune encephalomyelitis (EAE) murine model of MS. PSEN1 is the catalytic subunit of γ-secretase a multimo-lecular protease that mediates intramembranous proteolysis. γ-secretase is known to regulate several pathways of immune importance. Here we examine the effects of disrupting PSEN1 functions on EAE and T effector differentiation using small molecule inhibitors of γ-secretase (GSI) and T cell-specific conditional knockout mice (PSEN1 cKO). Surprisingly, blocking PSEN1 function by GSI treatment or PSEN1 cKO had little effect on the development or course of MOG35-55-induced EAE. In vivo GSI administration reduced the number of myelin antigen-specific T cells and suppressed Th1 and Th17 differentiation following immunization. In vitro, GSI treatment inhibited Th1 differentiation in neutral but not IL-12 polarizing conditions. Th17 differentiation was also suppressed by the presence of GSI in all conditions and GSI-treated Th17 T cells failed to induce EAE following adoptive transfer. PSEN cKO T cells showed reduced Th1 and Th17 differentiation. We conclude that γ-secretase and PSEN1-dependent signals are involved in T effector responses in vivo and potently regulate T effector differentiation in vitro, however, they are dispensable for EAE.

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U2 - 10.1371/journal.pone.0200752

DO - 10.1371/journal.pone.0200752

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JO - PLoS ONE

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ER -

ID: 40337499