Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo

J Exp Med. 1995 Nov 1;182(5):1201-12. doi: 10.1084/jem.182.5.1201.

Abstract

Neurons have evolved strategies to evade immune surveillance that include an inability to synthesize the heavy chain of the class I major histocompatibility complex (MHC), proteins that are necessary for cytotoxic T lymphocyte (CTL) recognition of target cells. Multiple viruses have taken advantage of the lack of CTL-mediated recognition and killing of neurons by establishing persistent neuronal infections and thereby escaping attack by antiviral CTL. We have expressed a class I MHC molecule (Db) in neurons of transgenic mice using the neuron-specific enolase (NSE) promoter to determine the pathogenic consequences of CTL recognition of virally infected, MHC-expressing central nervous system (CNS) neurons. The NSE-Db transgene was expressed in H-2b founder mice, and transgene-derived messenger RNA was detected by reverse transcriptase-polymerase chain reaction in transgenic brains from several lines. Purified primary neurons from transgenic but not from nontransgenic mice adhered to coverslips coated with a conformation-dependent monoclonal antibody directed against the Dv molecule and presented viral peptide to CTL in an MHC-restricted manner, indicating that the Db molecule was expressed on transgenic neurons in a functional form. Transgenic mice infected with the neurotropic lymphocytic choriomeningitis virus (LCMV) and given anti-LCMV, MHC-restricted CTL displayed a high morbidity and mortality when compared with controls receiving MHC-mismatched CTL or expressing alternative transgenes. After CTL transfer, transgenic brains showed an increased number of CD8+ cells compared with nontransgenic controls as well as an increased rate of clearance of infectious virus from the CNS. Additionally, an increase in blood-brain barrier permeability was detected during viral clearance in NSE-Db transgenic mice and lasted several months after clearance of virus from neurons. In contrast, LCMV-infected, nontransgenic littermates and mice expressing other gene products from the NSE promoter showed no CNS disease, no increased intraparenchymal CTL, and no blood-brain barrier damage after the adoptive transfer of antiviral CTL. Our study indicates that viral infections and CTL-CNS interactions may induce blood-brain barrier disruptions and neurologic disease by a "hit-and-run" mechanism, triggering a cascade of pathogenic events that proceeds in the absence of continual viral stimulation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blood-Brain Barrier
  • Cytotoxicity, Immunologic
  • Gene Expression Regulation
  • H-2 Antigens / biosynthesis
  • H-2 Antigens / genetics
  • H-2 Antigens / immunology*
  • Histocompatibility Antigen H-2D
  • Immunotherapy, Adoptive
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Molecular Sequence Data
  • Neurons / immunology*
  • Phosphopyruvate Hydratase / genetics
  • Promoter Regions, Genetic
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transgenes

Substances

  • H-2 Antigens
  • Histocompatibility Antigen H-2D
  • Recombinant Fusion Proteins
  • Phosphopyruvate Hydratase