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

Abstract

Abstract 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 CD8 T cells in the CNS have been described using multiple models of brain infections, but it is unknown whether CNS infection is required for development of brain Trm populations. Here, we show that peripheral infections and immunizations generate robust antigen (Ag)-specific CD8 memory T cells in the brain that adopt a Trm phenotype with a unique brain resident signature not prevalent in other organs. Upon peripheral antibody mediated depletion of circulating memory T cells, this brain signature was enriched without reducing proportion or number of CNS residing memory CD8 T cells. 2-photon microscopy revealed peripherally-induced Trm are highly dynamic in the CNS. 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, peripherally-induced Trm cells in the CNS showed enhanced cytokine production and provided protection against brain infections by reducing both bacterial and viral loads and morbidity and mortality associated with infections. These data increase our understanding of how peripheral immunization strategies can generate brain Trm populations and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.