Abstract
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.
Highlights
Tissue-resident memory T cells (TRM), the largest memory T cell subset, are non-recirculating cells parked in both nonlymphoid and lymphoid tissues [1,2,3]
Tissue resident memory cells (TRM) persist in nonlymphoid organs serving as frontline defense against microbial reinfection
We investigated the importance of CD4 T cell availability to CD8 TRM development during persistent viral encephalitis
Summary
Tissue-resident memory T cells (TRM), the largest memory T cell subset, are non-recirculating cells parked in both nonlymphoid and lymphoid tissues [1,2,3]. 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, those populated by large populations of non-renewable cells, such as the brain, where rapid control of infection may prove lifesaving. Little is known of the requirements for establishing and maintaining CD8 TRM cells to persistent viral CNS infections. Polyomaviruses are natural pathogens that persist as silent, lifelong infections in healthy hosts of many vertebrates. Thirteen polyomaviruses to date have been identified as constituents of the human virome, but several [BKPyV, JCPyV, and Merkel cell polyomavirus (MCPyV)] are opportunistic pathogens known to cause life-threatening diseases in immunocompromised individuals [6]. Deciphering the immunological deficits that predispose patients to PML remains to be determined
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