CONSEQUENCES OF CYTOTOXIC T-LYMPHOCYTE INTERACTION WITH MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-EXPRESSING NEURONS IN-VIVO

Neurons have evolved strategies to evade immune surveillance that incl ude an inability to synthesize the heavy chain of the class I major hi stocompatibility complex (MHC), proteins that are necessary for cytoto xic T lymphocyte (CTL) recognition of target cells. Multiple viruses h ave taken advantage of the lack of CTL-mediated recognition and killin g of neurons by establishing persistent neuronal infections and thereb y escaping attack by antiviral CTL. We have expressed a class I MHC mo lecule (D-b) in neurons of transgenic mice using the neuron-specific e nolase (NSE)promoter to determine the pathogenic consequences of CTL r ecognition of virally infected, MHC-expressing central nervous system (CNS) neurons. The NSE-D-b transgene was expressed in H-2(b) founder m ice, and transgene-derived messenger RNA was detected by reverse trans criptase-polymerase chain reaction in transgenic brains from several L ines. Purified primary neurons from transgenic but not from nontransge nic mice adhered to cover-slips coated with a conformation-dependent m onoclonal antibody directed against the D-b molecule and presented vir al peptide to CTL in an MHC-restricted manner, indicating that the D-b molecule was expressed on transgenic neurons in a functional form. Tr ansgenic mice infected with the neurotropic lymphocytic choriomeningit is virus (LCMV) and given anti-LCMV, MHC-restricted CTL displayed a hi gh morbidity and mortality when compared with controls receiving MHC-m ismatched CTL or expressing alternative transgenes. After CTL transfer , transgenic brains showed an increased number of CD8(+) cells compare d with nontransgenic controls as well as an increased rate of clearanc e of infectious virus from the CNS. Additionally, an increase in blood -brain barrier permeability was detected during viral clearance in NSE -D-b transgenic mice and lasted several months after clearance of viru s from neurons. In contrast, LCMV-infected, nontransgenic littermates and mice expressing other gene products from the NSE promoter showed n o CNS disease, no increased intraparenchymal CTL, and no blood-brain b arrier damage after the adoptive transfer of antiviral CTL. Our study indicates that viral infections and CTL-CNS interactions may induce bl ood-brain barrier disruptions and neurologic disease by a ''hit-and-ru n'' mechanism, triggering a cascade of pathogenic events that proceeds in the absence of continual viral stimulation.