CD8+ T cells target cerebrovasculature in children with cerebral malaria
Brittany A. Riggle, … , Dorian B. McGavern, Susan K. Pierce
Brittany A. Riggle, … , Dorian B. McGavern, Susan K. Pierce
Published December 10, 2019
Citation Information: J Clin Invest. 2020;130(3):1128-1138. https://doi.org/10.1172/JCI133474.
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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 4

Granzyme B–loaded CD8+ T cells target cerebrovasculature during CM.

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Granzyme B–loaded CD8+ T cells target cerebrovasculature during CM. Show...
Shown are representative confocal images captured from a CM+ Seqhi HIV– patient brain section. Images depict the distribution of granzyme B (green) and CD8+ T cells (red) in relation to CD31+ (white) cerebrovasculature and autofluorescent RBCs (orange). Representative RBCs in A and B are denoted with small white asterisks. The vascular lumen is denoted with large yellow asterisks or the word “lumen.” The dotted pink lines in C and D delineate the border of the blood vessel walls. Cyan arrowheads denote granzyme B+ CD8+ T cells engaged with (A–C) or depositing granzyme B+ onto (D) CD31+ vasculature. The pink arrowheads in A denote a CD8– granzyme B+ cell. Scale bars: 10 μm (A and B), 4 μm (C), and 2 μm (D).