Peripherally induced tissue resident memory CD8 T cells in the brain mediate protection against CNS infections

The central nervous system (CNS) is classically viewed as an immune privileged site; however recent advances in the field highlight the importance between the interaction of the peripheral immune system and the CNS in maintaining tissue homeostasis. Tissue resident memory (Trm) CD8 T cells have been described in almost every organ and are shown to provide a first line of defense against secondary invading pathogens. Trm cell generation generally involves active infection at the site of tissue residence. Using multicolor flow cytometry, we describe an increased representation of antigen-specific (Ag) CD8 T cells in the CNS after peripheral systemic immunizations or infections. Utilizing unbiased SPADE analysis, the intravascular (IV) stain negative Ag-specific tissue residing cells isolated from the CNS were phenotypically distinct from the IV stain positive cells in the vasculature. Further characterization indicated peripherally-induced CD8 T cells residing in the brain adopted a Trm phenotype and were resistant to systemic antibody-mediated depletion. The increased representation and phenotype of CD8 T cells in the brain after systemic immunization was similarly found in the meninges but not in peripheral organs including liver or lungs. 2-photon microscopy revealed peripherally-induced Trm are highly dynamic in the brain. CD8 T cells surveyed the tissue with multiple mechanisms including moving along the blood vessels, traveling long distances in apparently random fashion or remaining stationary. Most importantly, systemically-induced Trm cells in the CNS provided protection against neurotropic challenges by reducing bacterial and viral loads and limiting morbidity and mortality associated with the infections.