Regional Distribution of CNS Antigens Differentially Determines T-Cell Mediated Neuroinflammation in a CX3CR1-Dependent Manner

J Neurosci. 2018 Aug 8;38(32):7058-7071. doi: 10.1523/JNEUROSCI.0366-18.2018. Epub 2018 Jun 29.

Abstract

T cells continuously sample CNS-derived antigens in the periphery, yet it is unknown how they sample and respond to CNS antigens derived from distinct brain areas. We expressed ovalbumin (OVA) neoepitopes in regionally distinct CNS areas (Cnp-OVA and Nes-OVA mice) to test peripheral antigen sampling by OVA-specific T cells under homeostatic and neuroinflammatory conditions. We show that antigen sampling in the periphery is independent of regional origin of CNS antigens in both male and female mice. However, experimental autoimmune encephalomyelitis (EAE) is differentially influenced in Cnp-OVA and Nes-OVA female mice. Although there is the same frequency of CD45high CD11b+ CD11c+ CX3CL1+ myeloid cell-T-cell clusters in neoepitope-expressing areas, EAE is inhibited in Nes-OVA female mice and accelerated in CNP-OVA female mice. Accumulation of OVA-specific T cells and their immunomodulatory effects on EAE are CX3C chemokine receptor 1 (CX3CR1) dependent. These data show that despite similar levels of peripheral antigen sampling, CNS antigen-specific T cells differentially influence neuroinflammatory disease depending on the location of cognate antigens and the presence of CX3CL1/CX3CR1 signaling.SIGNIFICANCE STATEMENT Our data show that peripheral T cells similarly recognize neoepitopes independent of their origin within the CNS under homeostatic conditions. Contrastingly, during ongoing autoimmune neuroinflammation, neoepitope-specific T cells differentially influence clinical score and pathology based on the CNS regional location of the neoepitopes in a CX3CR1-dependent manner. Altogether, we propose a novel mechanism for how T cells respond to regionally distinct CNS derived antigens and contribute to CNS autoimmune pathology.

Keywords: CNS; T cells; autoimmunity; neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',3'-Cyclic-Nucleotide Phosphodiesterases / genetics
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CX3C Chemokine Receptor 1 / physiology*
  • Central Nervous System / immunology*
  • Chemokine CX3CL1 / physiology
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • Genes, Synthetic
  • Mice
  • Mice, Transgenic
  • Myelin-Oligodendrocyte Glycoprotein / genetics
  • Myelin-Oligodendrocyte Glycoprotein / immunology*
  • Nestin / genetics
  • Neural Stem Cells / immunology*
  • Neuroimmunomodulation / physiology*
  • Oligodendroglia / immunology*
  • Organ Specificity
  • Peptide Fragments / genetics
  • Peptide Fragments / immunology
  • Promoter Regions, Genetic
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • T-Lymphocyte Subsets / immunology*

Substances

  • CX3C Chemokine Receptor 1
  • Chemokine CX3CL1
  • Cx3cl1 protein, mouse
  • Cx3cr1 protein, mouse
  • Myelin-Oligodendrocyte Glycoprotein
  • Nestin
  • Peptide Fragments
  • Recombinant Proteins
  • myelin oligodendrocyte glycoprotein (35-55)
  • 2',3'-Cyclic-Nucleotide Phosphodiesterases