Protective Immunosurveillance of the Central Nervous System by Listeria-Specific CD4 and CD8 T Cells in Systemic Listeriosis in the Absence of Intracerebral Listeria

Abstract

The invasion of the CNS by pathogens poses a major risk for damage of the highly vulnerable brain. The aim of the present study was to analyze immunological mechanisms that may prevent spread of infections to the CNS. Intraperitoneal application of Listeria monocytogenes to mice induced infection of the spleen, whereas pathogens remained absent from the brain. Interestingly, Listeria-specific CD4 and CD8 T cells homed to the brain and persisted intracerebrally for at least 50 days after both primary and secondary infection. CD4 and CD8 T cells resided in the leptomeninges, in the choroid plexus, and, in low numbers, in the brain parenchyma. CD4 and CD8 T cells isolated from the brain early after infection (day 7) were characterized by an activated phenotype with spontaneous IFN-γ production, whereas at a later stage of infection (day 28) restimulation with Listeria-specific peptides was required for the induction of IFN-γ production by CD4 and CD8 T cells. In contrast to splenic T cells, T cells in the brain did not exhibit cytotoxic activity. Adoptively transferred T cells isolated from the brains of Listeria-infected mice reduced the bacterial load in cerebral listeriosis. The frequency of intracerebral Listeria-specific T cells was partially regulated by the time of exposure to Listeria and cross-regulated by CD4 and CD8 T cells. Collectively, these data reveal a novel T cell-mediated pathway of active immunosurveillance of the CNS during bacterial infections.

The Ly-6Chigh Monocyte Subpopulation Transports Listeria monocytogenes into the Brain during Systemic Infection of Mice

“…This is similar to recent data in systemic listeriosis in mice showing that Listeriaspecific T cells also enter the brain in the absence of CNS infection (42). Our finding that monocytes enter the brain before neutrophils contrasts with the sequence reported by others.…”

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

“…Thus, our data provide evidence that modulation of CD8 + T cell function is a potential strategy to improve therapy against a wide range of diseases that occur in the brain. Given the proposed roles for CD8 + T cells in mediating or protecting against numerous brain-related diseases, such as viral encephalitis (58)(59)(60), toxoplasmosis (61,62), multiple sclerosis (63-65), brain tumors (29,31,66), and cerebral listeriosis (67)(68)(69), our data have implications that extend beyond ECM to other infectious diseases, cancer, and autoimmunity.…”

Mini‐review: Presentation of pathogen‐derived antigens in vivo

“…Likewise, mice that have been infected intraperitoneally exhibit 10-100-fold fewer bacteria in their spleen as compared with intravenously infected mice [24,25]. Further analysis of the infection after intravenous or oral inoculation revealed comparable kinetics of bacterial growth and spreading in spleen, liver and mesenteric LN.…”