Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping

Cell. 2018 Oct 4;175(2):458-471.e19. doi: 10.1016/j.cell.2018.07.049. Epub 2018 Aug 30.


Inflammatory disorders of the CNS are frequently accompanied by synaptic loss, which is thought to involve phagocytic microglia and complement components. However, the mechanisms accounting for aberrant synaptic connectivity in the context of CD8+ T cell-driven neuronal damage are poorly understood. Here, we profiled the neuronal translatome in a murine model of encephalitis caused by CD8+ T cells targeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2 expression were essential for apposition of phagocytes, ensuing synaptic loss and neurological disease. Analogous observations were made in the brains of Rasmussen's encephalitis patients. In this devastating CD8+ T cell-driven autoimmune disease, neuronal STAT1 phosphorylation and CCL2 expression co-clustered with infiltrating CD8+ T cells as well as phagocytes. Taken together, our findings uncover an active role of neurons in coordinating phagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 as critical steps in this process that are amenable to pharmacological interventions.

Keywords: Rasmussen’s encephalitis; cytotoxic T cells; neuroinflammation; phagocytes; synapse loss.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / physiology
  • Disease Models, Animal
  • Encephalitis / genetics
  • Encephalitis / immunology
  • Encephalitis / physiopathology
  • Female
  • Humans
  • Inflammation / immunology
  • Inflammation / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Nervous System Diseases / metabolism
  • Neurons / metabolism*
  • Neurons / physiology
  • Phagocytes / immunology
  • Phagocytes / metabolism
  • Phagocytosis / immunology
  • Phagocytosis / physiology*
  • Phosphorylation
  • STAT1 Transcription Factor / physiology
  • Synapses / physiology*
  • Transcriptome / genetics


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse

Supplementary concepts

  • Rasmussen subacute encephalitis