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Presenilin1 regulates Th1 and Th17 effector responses but is not required for experimental autoimmune encephalomyelitis
Journal article   Open access   Peer reviewed

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

Matthew Cummings, Anitha Christy Sigamani Arumanayagam, Picheng Zhao, Sunil Kannanganat, Olaf Stuve, Nitin J Karandikar and Todd N Eagar
PloS one, Vol.13(8), pp.e0200752-e0200752
2018
DOI: 10.1371/journal.pone.0200752
PMCID: PMC6082653
PMID: 30089166
url
https://doi.org/10.1371/journal.pone.0200752View
Published (Version of record) Open Access

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 multimolecular 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.
 Granulocyte-Macrophage Colony-Stimulating Factor - metabolism Encephalomyelitis, Autoimmune, Experimental - immunology Th1 Cells - immunology Th1 Cells - metabolism Dibenzazepines - pharmacology Th17 Cells - drug effects Dibenzazepines - therapeutic use Th17 Cells - metabolism Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism Female Interleukin-2 - metabolism Th1 Cells - drug effects Encephalomyelitis, Autoimmune, Experimental - pathology Encephalomyelitis, Autoimmune, Experimental - drug therapy Mice, Inbred C57BL Presenilin-1 - genetics Mice, Knockout Interleukin-17 - metabolism Amyloid Precursor Protein Secretases - metabolism Animals Cell Differentiation - drug effects Th17 Cells - immunology Cell Proliferation - drug effects Mice Amyloid Precursor Protein Secretases - antagonists & inhibitors Presenilin-1 - deficiency

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