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Comparative Study
. 2019 Jul 24:10:1747.
doi: 10.3389/fimmu.2019.01747. eCollection 2019.

Comparison of CD8+ T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria

Valentina Barrera  1 , Michael J Haley  2 , Patrick Strangward  2 , Elizabeth Attree  1 , Steve Kamiza  3 , Karl B Seydel  4   5 , Terrie E Taylor  4   5 , Danny A Milner Jr  6 , Alister G Craig  7 , Kevin N Couper  2
Affiliations
Comparative Study

Comparison of CD8+ T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria

Valentina Barrera et al. Front Immunol. .

Abstract

CD8+ T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. Thus, in this study we have provided the first direct contrast of the accumulation of CD8+ T cells in the brain during HCM and ECM. HCM cases were from children who died of Plasmodium falciparum cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 and 2010. ECM was induced by infecting C57BL/6J mice with P. berghei ANKA. We demonstrate similarities in the intracerebral CD8+ T cell responses in ECM and HCM, in particular an apparent shared choroid plexus-meningeal route of CD8+ T cell accumulation in the brain. Nevertheless, we also reveal some potentially important differences in compartmentalization of CD8+ T cells within the cerebrovascular bed in HCM and ECM.

Keywords: CD8+ T cells; Plasmodium berghei; Plasmodium falciparum; brain; cerebral malaria.

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Figures

Figure 1
Figure 1
Distribution of intracerebral CD8+ T cells in the cortex in HCM and ECM. The presence of intracerebral CD8+ T cells was assessed by immunohistochemistry in fatal HCM cases, in C57BL/6 mice that developed late-stage ECM after Pb ANKA infection, and in appropriate controls. (A) Representative images from HCM and ECM cases showing (Ai) low magnification and (Aii) high magnification identification of both luminal (black arrows) and perivascular (gray arrows) CD8+ T cells, in capillaries and large caliber vessels. (Aiii) Representative images showing lack of CD8+ T cells in brains of HCM controls (CM9) and naïve mice. (B) Several parameters of CD8+ T cell accumulation were quantified: (Bi) absolute numbers of CD8+ T cells per mm2, (Bii) percentage of total vessels with CD8+ T cells (either luminal or perivascular), (Biii) percentage of CD8+ T cells that were perivascular, (Biv) percentage of vessels in HCM cases with CD8+ T cells separated into vessels with and without parasitized red blood cells (pRBCs). HCM = CM1 (filled circles) and CM2 (open circles) cases, Non-HCM = CM3 (filled circles) and CM7 (open circles), Non-Inf = CM9 (filled circles) and CM11 (open circles). (C) Representative images from HCM cases and ECM samples showing: (Ci) intracerebral hemorrhage (white arrows indicate red blood cells, note classical ring hemorrhage in HCM, demarcated by dotted outline), areas of vasogenic edema (asterisks) without (Cii) and with CD8+ T cells (Ciii). Scale bars = 50 μm. *p < 0.05. Human cases were compared by one-way ANOVA with Holm-Sidak's multiple comparisons test, ECM was compared to naïve by Student's t-test, and presence of CD8+ T cells in pRBC positive and negative vessels was compared by Student's t-test.
Figure 2
Figure 2
Distribution of CD8+ T cells in the leptomeninges and choroid plexus in HCM and ECM. The presence of CD8+ T cells in the leptomeninges and choroid plexus was assessed by immunohistochemistry in fatal HCM cases, in C57BL/6 mice that developed late-stage ECM after Pb ANKA infection, and in appropriate controls. (A) Representative images of the leptomeninges from HCM and ECM cases showing CD8+ T cells in the lumen of pial vessels (black arrows), and in the subarachnoid space (gray arrows). (B) Representative images of the choroid plexus from HCM and ECM cases showing CD8+ T cells in the stroma or lumen (asterisks) of blood vessels (black arrows), or that have transmigrated into the ventricle (gray arrows; white triangle indicates CSF-filled ventricle). (C) (Ci) Absolute numbers of CD8+ T cells per mm2 of choroid plexus; (Cii) percentage of CD8+ T cells in the choroid plexus that had transmigrated into the ventricle. HCM = CM1 (filled circles) and CM2 (open circles) cases, Non-HCM = CM3 (filled circles) and CM7 (open circles), Non-Inf = CM9 (filled circles) and CM11 (open circles). Scale bars = 50 μm. *p < 0.05. Human cases were compared by one-way ANOVA with Holm-Sidak's multiple comparisons test, ECM was compared to naïve by Students t-test.
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