Group A streptococcal (GAS) infection induces the production of Abs that cross-react with host neuronal proteins, and these anti-GAS mimetic Abs are associated with autoimmune diseases of the CNS. However, the mechanisms that allow these Abs to cross the blood-brain barrier (BBB) and induce neuropathology remain unresolved. We have previously shown that GAS infection in mouse models induces a robust Th17 response in nasal-associated lymphoid tissue (NALT). Here, we identified GAS-specific Th17 cells in tonsils of humans naturally exposed to GAS, prompting us to explore whether GAS-specific CD4+ T cells home to mouse brains following i.n. infection. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB. Together, these findings provide insight into the immunopathology of neuropsychiatric complications that are associated with GAS infections and suggest that crosstalk between the CNS and cellular immunity may be a general mechanism by which infectious agents exacerbate symptoms associated with other CNS autoimmune disorders.
Bibliographical noteFunding Information:
We thank Holly and Mark Kerslake from Newport Equities LLC for their generous financial support that made much of this work possible; Ilir Agalliu of the Albert Einstein College of Medicine for help with statistical analysis; Tyler Cutforth for advice on the olfactory system anatomy and olfactory circuitry synapses and for providing critical scientific and editorial input regarding the manuscript; Marc Jenkins for providing 2W:I-Ab tetramers; Vaiva Vezys for guidance with the isolation of brain T cells; and Edward Kaplan for suggesting the cribriform plate as a possible window for T cell entry into the brain. E.D. Smith, D. Knowland, M. Hsu, M. Platt, and D. Agalliu are supported by grants from the National Heart, Lung, and Blood Institute (NHLBI), NIH (7R01 HL116995-01), the National Multiple Sclerosis Society (NMSS) (RG4673A1/1), and by a generous donation from Newport Equities LLC. Portions of this work were funded by pandasnetwork.org and by P.P. Cleary, from a royalty account at the University of Minnesota. The confocal facility in the Optical Biology Shared Resource at the University of California, Irvine, was funded by a Cancer Center Support Grant (CA-62203).