Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells
Thamotharampillai Dileepan, … , Dritan Agalliu, P. Patrick Cleary
Thamotharampillai Dileepan, … , Dritan Agalliu, P. Patrick Cleary
Published December 14, 2015
Citation Information: J Clin Invest. 2016;126(1):303-317. https://doi.org/10.1172/JCI80792.
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Research Article Immunology

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells

Abstract

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.

Authors

Thamotharampillai Dileepan, Erica D. Smith, Daniel Knowland, Martin Hsu, Maryann Platt, Peter Bittner-Eddy, Brenda Cohen, Peter Southern, Elizabeth Latimer, Earl Harley, Dritan Agalliu, P. Patrick Cleary

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Figure 1

Human tonsils contain GAS-specific effector memory Th17 cells.

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Human tonsils contain GAS-specific effector memory Th17 cells. (A) Repre...
(A) Representative FACS plots of IL-17A+ or IFN-γ+CD4+ T cells from the tonsils of 1 patient. Single-cell suspensions were incubated for 6 hours with PBS (control), HK-GAS, or PMA+I prior to analysis. Numbers within panels indicate the percentages of total CD4+ T cells that expressed specific cytokines. (B) Scatter plot of cytokine expression as a percentage of total CD4+ T cells analyzed in tissues from 28 patients. Each dot represents an individual patient. Horizontal lines indicate the mean percentage of cytokine-producing cells. Statistical significance of mean differences was assessed with the Wilcoxon matched-pairs signed-rank test. Data are representative of 10 experiments. (C) FACS plots for HK-GAS–activated tonsil cells stained for IL-17A, CD4, CD45RO, and CD45RA. Cells shown at the top of the IL-17A/CD4 panel and in the left panel for CD45RO/CD45RA were gated on IL-17A+CD4+ T cells, and cells at the bottom of the IL-17A/CD4 panel and in the right panel for CD45RO/CD45RA were gated on IL-17A–CD4+ T cells. (D) Bar graph shows the fold increase in CD4+IL-17A+ cells after single-cell suspensions from 1 patient were incubated with PBS (white), HK-GAS (black), L. lactis (light gray), or HK-GAS, a Sag– strain that lacks all known superantigen genes (23) (dark gray). Bar graphs show the mean ± SEM.