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

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.

Autophagy Is a Tolerance-Avoidance Mechanism that Modulates TCR-Mediated Signaling and Cell Metabolism to Prevent Induction of T Cell Anergy

“…Other studies have also reported protective effects of chloroquine on EAE and have identified other mechanisms, including inhibition of autophagy in dendritic cells and increased Treg differentiation ( Thome´ et al, 2013 , 2014 ). Furthermore, Atg5 deletion in dendritic cells prevents presentation of phagocytosed oligodendrocyte proteins and protects against EAE ( Keller et al, 2017 ). It is therefore likely that the role of autophagy in autoimmunity extends beyond the intrinsic regulation of T cell tolerance to include other mechanisms such as T cell differentiation and antigen presentation.…”

Exploring the Role of Autophagy-Related Gene 5 (ATG5) Yields Important Insights Into Autophagy in Autoimmune/Autoinflammatory Diseases

“…Recent studies have revealed the role of autophagy and CNS autoimmunity, in which ATG5 might play an important role. ATG5 in dendritic cells is regarded as a possible autoimmune response driver, according to a study in which Atg5 -deleted mice exhibited lower degree of demyelination in the CNS ( 152 ). In the absence of ATG5, CD4+ T cell presentation of endogenous myelin peptides was inhibited, which restricted the downstream autoimmune response ( 152 , 153 ).…”

Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice

“…CNS tissues from huNSG-A2 mice were isolated as previously described [67]. In brief, animals were perfused with ice-cold PBS, CNS was removed, dissected into small pieces, suspended in digest buffer (collagenase D 0.2 mg/ml; DNAse 20 μg/ml in PBS), and incubated for 40min at 37˚C and 5% CO 2 .…”