TUBITAK Destekli Projelerden Çıkan Yayınlar Topluluğu
Published January 1, 2025 | Version v1
Journal article Open

Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis

Creators

  • 1. Univ Genoa, Dept Expt Med, Genoa, Italy
  • 2. Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA
  • 3. Sorbonne Univ, Hop Pitie Salpetriere Univ Ho, AP HP,CIC Neurosci, INSERM,CNRS,Paris Brain Inst ICM,Inst Cerveau, Paris, France
  • 4. Univ Miami, Dept Pediat, Div Neonatol, Miami, FL USA
  • 5. Univ Genoa, Dept Internal Med DIMI, Genoa, Italy
  • 6. CNR, Ist Applicazioni Calcolo M Picone, Naples, Italy

Description

The immune regulatory defects that promote neuroinflammation in multiple sclerosis (MS) remain unclear. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 was increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3+ Treg cells were induced by the gut microbiota via Toll-like receptor (TLR)-dependent mechanisms. They then translocated to the central nervous system (CNS) in EAE where they promoted disease severity. Notch3 interacted with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. Notch3 deletion in Treg cells prevented EAE onset by stabilizing Treg cells and by simultaneously promoting the expansion of a tissue-resident Treg cell population that expressed neuropeptide Y receptor 1 (NPY1R) and which suppressed pathogenic IFN-gamma+ and GM-CSF+ T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation.

Files

bib-3f64fd7e-c7c2-4084-94fe-85409bc25378.txt

Files (402 Bytes)

Name Size Download all
md5:792cd37039d00dc723a259ea7f43cee5
402 Bytes Preview Download