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Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11228-E11237. doi: 10.1073/pnas.1713664114. Epub 2017 Dec 12.

ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation.

Author information

1
Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, 8057 Zurich, Switzerland.
2
Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland.
3
Institute of Experimental Immunology, Laboratory of Inflammation Research, University of Zurich, 8057 Zurich, Switzerland.
4
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
5
Institute of Experimental Immunology, Laboratory of Viral Immunobiology, University of Zurich, 8057 Zurich, Switzerland.
6
Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, 8057 Zurich, Switzerland; jan.luenemann@uzh.ch.
7
Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland.

Abstract

Although reactivation and accumulation of autoreactive CD4+ T cells within the CNS are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the mechanisms of how these cells recognize their target organ and induce sustained inflammation are incompletely understood. Here, we report that mice with conditional deletion of the essential autophagy protein ATG5 in classical dendritic cells (DCs), which are present at low frequencies in the nondiseased CNS, are completely resistant to EAE development following adoptive transfer of myelin-specific T cells and show substantially reduced in situ CD4+ T cell accumulation during the effector phase of the disease. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells is abrogated in the absence of ATG5. Pharmacological inhibition of ATG-dependent phagocytosis by the cardiac glycoside neriifolin, an inhibitor of the Na+, K+-ATPase, delays the onset and reduces the clinical severity of EAE induced by myelin-specific CD4+ T cells. These findings link phagocytosis of injured oligodendrocytes, a pathological hallmark of MS lesions and during EAE, with myelin antigen processing and T cell pathogenicity, and identify ATG-dependent phagocytosis in DCs as a key regulator in driving autoimmune CD4+ T cell-mediated CNS damage.

KEYWORDS:

EAE; autophagy; multiple sclerosis; neuroinflammation

PMID:
29233943
PMCID:
PMC5748192
DOI:
10.1073/pnas.1713664114
[Indexed for MEDLINE]
Free PMC Article

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