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 5

Impact of HIV infection on the accumulation of CD8+ T cells in venous cerebrovasculature.

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Impact of HIV infection on the accumulation of CD8+ T cells in venous ce...
Representative images of brain sections from CM+ Seqhi HIV+ (A), CM+ Seqhi HIV– (B), and CM– Seq0 HIV+ (C) children. Images show the distribution of CD3+ (red), CD8+ (green) T cells in relation to CD31+ (white) cerebrovasculature. DAPI-stained cell nuclei are shown in blue. Yellow asterisks denote the vascular lumen. Scale bars: 20 μm. Normalized counts of luminal, abluminal, and total CD3+CD8+ T cells/vessel area (log2((number of cells/μm2/104) + 2) are provided in D–F. Each symbol represents the number of CD3+CD8+ T cells/vessel area for 1 of the 20 vessels examined per child. In CM+ Seqhi children, HIV coinfection was associated with a decrease in CD3+ CD8+ T cells/vessel area, luminally (D, n = 8 for both; FDR P = 0.004). Conversely, in CM+ Seqhi children, HIV coinfection was associated with an increase in CD3+CD8+ T cells/vessel area abluminally. HIV+ cases with (n = 8) or without CM (n = 4) also showed significantly more CD3+CD8+ T cells/vessel area abluminally than cases without HIV (n = 8) coinfection (E, FDR P < 0.0001 and FDR P < 0.005, respectively). Furthermore, CM+ Seqhi HIV+ children had a greater total number of CD3+ CD8+ T cells/vessel area compared with CM+ Seqhi HIV– (F, FDR P < 0.017). 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 conditions 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 ≤ 0.01; ****P < 0.0001.