CD4 T cells control development and maintenance of brain-resident CD8 T cells during polyomavirus infection

Tissue-resident memory CD8 T (TRM) cells defend against microbial reinfections at mucosal barriers; determinants driving durable TRM cell responses in non-mucosal tissues, which often harbor opportunistic persistent pathogens, are unknown. JC polyomavirus (JCPyV) is a ubiquitous constituent of the human virome. With altered immunological status, JCPyV can cause the oft-fatal brain demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV is a human-only pathogen. Using the mouse polyomavirus (MuPyV) encephalitis model, we demonstrate that CD4 T cells regulate development of functional antiviral brain-resident CD8 T cells (bTRM) and renders their maintenance refractory to systemic CD8 T cell depletion. Acquired CD4 T cell deficiency, modeled by delaying systemic CD4 T cell depletion until MuPyV-specific CD8 T cells have infiltrated the brain, impacted the stability of CD8 bTRM, impaired their effector response to reinfection, and rendered their maintenance dependent on circulating CD8 T cells. This dependence of CD8 bTRM differentiation on CD4 T cells was found to extend to encephalitis caused by vesicular stomatitis virus. Together, these findings reveal an intimate association between CD4 T cells and homeostasis of functional bTRM to CNS viral infection.
Author summary Tissue resident memory cells (TRM) persist in nonlymphoid organs serving as frontline defense against microbial reinfection. The requirements for generating pathogen-specific TRM to acutely resolved infections is well documented; however, little is known about the development of TRM to persistent infections. In this study, we investigated the importance of CD4 T cell availability to CD8 TRM development during persistent viral encephalitis. Using mouse polyomavirus (MuPyV) brain infection and systemic CD4 T cell insufficiency, we found that loss of CD4 T cells abrogated brain TRM (bTRM) development, disrupted the metabolic homeostasis of CD8 T cells, and reduced CD8 T cell responses upon viral reinfection. Additionally, CD8 T cells in CD4 T cell-deficient mice required resupply from circulating CD8 T cells, directly contrasting the independence from circulation in canonical TRM. Upon delayed CD4 T cell depletion and brain infection with an acutely resolving viral infection, CD8 T cells also had aberrant bTRM development and required resupply from the vasculature. Our findings demonstrate that CD4 T cells are essential for establishing long-lasting, virus-specific CD8 bTRM for antiviral CNS immunosurveillance. Our data also raise important clinical implications for developing therapies to augment CD4 T cell help to bolster protective CD8 bTRM responses.