CD8+ T cells target cerebrovasculature in children with cerebral malaria
Brittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, Susan K. Pierce
Brittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, Susan K. Pierce
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Clinical Research and Public Health Infectious disease Neuroscience

CD8+ T cells target cerebrovasculature in children with cerebral malaria

Abstract

BACKGROUND Cerebral malaria (CM) accounts for nearly 400,000 deaths annually in African children. Current dogma suggests that CM results from infected RBC (iRBC) sequestration in the brain microvasculature and resulting sequelae. Therapies targeting these events have been unsuccessful; findings in experimental models suggest that CD8+ T cells drive disease pathogenesis. However, these data have largely been ignored because corroborating evidence in humans is lacking. This work fills a critical gap in our understanding of CM pathogenesis that is impeding development of therapeutics.METHODS Using multiplex immunohistochemistry, we characterized cerebrovascular immune cells in brain sections from 34 children who died from CM or other causes. Children were grouped by clinical diagnosis (CM+ or CM–), iRBC sequestration (Seqhi, Seqlo, Seq0) and HIV status (HIV+ or HIV–).RESULTS We identified effector CD3+CD8+ T cells engaged on the cerebrovasculature in 69% of CM+ HIV– children. The number of intravascular CD3+CD8+ T cells was influenced by CM status (CM+ > CM–, P = 0.004) and sequestration level (Seqhi > Seqlo, P = 0.010). HIV coinfection significantly increased T cell numbers (P = 0.017) and shifted cells from an intravascular (P = 0.004) to perivascular (P < 0.0001) distribution.CONCLUSION Within the studied cohort, CM is associated with cerebrovascular engagement of CD3+CD8+ T cells, which is exacerbated by HIV coinfection. Thus, CD3+CD8+ T cells are highly promising targets for CM adjunctive therapy, opening new avenues for the treatment of this deadly disease.FUNDING This research was supported by the Intramural Research Program of the National Institutes of Health.

Authors

Brittany A. Riggle, Monica Manglani, Dragan Maric, Kory R. Johnson, Myoung-Hwa Lee, Osorio Lopes Abath Neto, Terrie E. Taylor, Karl B. Seydel, Avindra Nath, Louis H. Miller, Dorian B. McGavern, Susan K. Pierce

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Figure 3

Quantification of CD8+ T cells in cerebral arteries versus veins.

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Quantification of CD8+ T cells in cerebral arteries versus veins. Normal...
Normalized counts of CD3+CD8+ T cells per vessel area (log2((number of cells/μm2/104) + 2)) are described in A–E. Each symbol within a plot represents the normalized count of CD3+CD8+ T cells per vessel area for 1 of the 20 vessels examined for each child with the color denoting the vessel type (artery: blue; vein: red). A significant increase in venous CD3+CD8+ T cell counts was observed for CM+ Seqhi HIV– (A, n = 8; FDR P < 0.001) and CM+ Seqhi HIV+ (B, n = 8; FDR P = 0.035). No significant difference in normalized CD3+CD8+ T cell counts was observed between arteries and veins for CM+ Seqlo HIV– (C, n = 5), CM– Seq0 HIV– (D, n = 7), or CM– Seq0 HIV+ (E, n = 4). P values were obtained via post hoc analysis using the difflsmeans function under FDR correction conditions following mixed-effects modeling with the lmer function. Significant differences remained so under bootstrap condition 100% of time when any normalized cell count for a single vessel was removed or when all vessels for any 1 child were removed. Error bars represent mean ± SD. Asterisks denote statistical significance: FDR *P ≤ 0.05; ***P ≤ 0.001.