Date Published: October 29, 2018
Publisher: Public Library of Science
Author(s): Taryn E. Mockus, Matthew D. Lauver, Heather M. Ren, Colleen S. Netherby, Tarik Salameh, Yuka Imamura Kawasawa, Feng Yue, James R. Broach, Aron E. Lukacher, Walter J. Atwood.
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.
Tissue-resident memory T cells (TRM), the largest memory T cell subset, are non-recirculating cells parked in both nonlymphoid and lymphoid tissues [1–3]. The importance of CD8 TRM cells in limiting infections, their distinct transcriptional profile, the signals driving their differentiation, and their capacity to control reinfections at mucosal portals of pathogen entry are well documented [1, 4]. Far less is known about the requirements for establishing CD8 TRM cells in non-mucosal tissues, particularly those populated by large populations of non-renewable cells, such as the brain, where rapid control of infection may prove lifesaving. Recent studies using acutely resolved viral meningo-encephalitidies have revealed the durability of brain-resident memory CD8 (bTRM) cells and their role in clearing CNS viral infections . However, little is known of the requirements for establishing and maintaining CD8 TRM cells to persistent viral CNS infections.
CD4 T cells modulate the differentiation program of pathogen-specific CD8 T cells that establish permanent residence as memory cells in mucosal barrier tissues, but their role in driving TRM development in non-barrier tissues is less understood . In this study, we determined that CD4 T cell help was essential for establishment and maintenance of CD8 bTRM to MuPyV encephalitis. CD4 T cells guided the differentiation of MuPyV-specific CD8 bTRM during naïve T cell priming and were required for maintenance of functional antiviral CD8 bTRM in brains of persistently infected mice. Notably, CD4 T cell insufficiency resulted in diminished effector competence of antiviral CD8 T cells encountering MuPyV reinfection in the brain. An ongoing dependence on CD4 T cells for induction and maintenance of virus-specific CD8 bTRM to a persistent CNS infection has clear clinical implications for individuals whose immune status is altered by infection or immunomodulatory therapeutic agents.