Immune-mediated viral clearance from the CNS without collateral damage.

The events that lead to the control of many infections are frequently associated with immune-mediated collateral damage to surrounding cells and tissues. Nowhere is this more apparent than in the central nervous system (CNS), in part because of its immune privileged status. Lymphocytic choriomeningitis virus (LCMV) has provided a tractable model to study how antiviral effector responses, associated with chemokine production, lead to the recruitment of tissue-damaging myelomonocytes and fatal meningitis.

Insight from Christoph Konradt (left) and Christopher Hunter (right)

In this issue, Herz et al. report how “therapeutic T cells” derived from previously infected mice can clear LCMV from mice persistently infected from birth in the absence of collateral tissue damage. The authors found that the protective T cells did not express the chemokines typically associated with the recruitment of myelomonocytic cells that damage the blood–brain barrier and cause tissue damage. The therapeutic T cells themselves were not cytolytic but rather produced IFNγ, which induced viral clearance in microglial cells and in neuronal cells. Because neurons are not considered responsive to IFNγ, it remains to be determined whether and how the noncytopathic bystander clearance of viral infection is mediated. It was notable that in persistently infected mice, microglia were a major reservoir of infection and the use of intravital imaging and transcriptional profiling revealed that the T cells interacted with microglial cells and prompted these CNS-resident macrophages to proliferate and present antigen. Thus, these findings indicate a central role for the therapeutic T cells in licensing of microglia to purge virus, present antigen, and presumably amplify the local antiviral T cell response.

Therapeutic T cells produce IFNγ and interact with microglial cells to activate STAT1 and mediate viral clearance and promote their ability to present antigen and to proliferate. Associated with these events is the noncytolytic clearance of virus from neurons by an unknown bystander mechanism.

A key challenge for neuroimmunologists is to understand how to promote effector responses that mediate local antimicrobial responses in the CNS with minimal recruitment of pathological bystander cells. A better understanding of the pathways that lead to the generation of the therapeutic T cells used in this study and how they differ from those associated with pathology should provide clear insights into how to tailor a specific immune response to any given pathogen (or tumor) present in the CNS without causing immunopathology.