# CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $412,120

## Abstract

ABSTRACT
The most severe clinical complication of Plasmodium falciparum infection is cerebral malaria (CM) which has
high morbidity despite treatment. The spread of malaria is becoming increasingly more serious as Plasmodium
falciparum develops resistance to traditional drugs used to treat the condition. For the above reasons,
understanding the etiology of CM is critical to treat this highly significant global issue. Recently, more rigorous
large scale MRI studies have been conducted on CM patients. As previously hypothesized, disruption of the
blood-brain barrier (BBB), extensive edema, and brain swelling are associated with fatal human CM. Given the
above observations in human CM, the mechanism of BBB disruption and vascular permeability needs to be
defined. Plasmodium berghei ANKA (PbA) infection of mice is an established model of human CM.
Considerable CNS pathology associated with PbA infection is driven by an acute CD8 T cell response which
induces disruption of BBB tight junction proteins and CNS vascular permeability. Using our novel MHC class I
conditional knockout mice, we have determined that macrophages and dendritic cells prime non-equivalent
CD8 T cell responses in response to PbA infection. While both antigen presenting cells prime CD8 T cell
response that infiltrate the brain, only CD8 T cells raised by dendritic cells induce lethal blood-brain barrier
disruption. Our central hypothesis is that specific APC subsets, namely macrophages, microglia, and
dendritic cells, contribute to the generation distinct brain infiltrating CD8 T cell responses against PbA
infection. These distinct CD8 T cell responses have differential ability to induce fatal BBB disruption.
We plan to test this central hypothesis through execution of the following specific aims:
Specific Aim #1 – Define the brain infiltrating CD8 T cell repertoire raised by LysM+ and CD11c+ APCs
during acute PbA infection.
Specific Aim #2 – Identify the CD11c+ APC required for CD8 T cell mediated BBB disruption.
Specific Aim #3 – Determine the capacity of CD8 T cell populations primed by distinct antigen
presenting cell types to inflict BBB disruption during the effector phase of PbA infection.
The proposed work is innovative because it capitalizes on our unique transgenic mouse models, novel imaging
methodology, and new core facilities available to our research program at Mayo Clinic. Our goal is to define
mechanistically the contribution of inflammation to BBB disruption in experimental human CM through
knowledge gained using a leading experimental model. Beyond the innovative methodology employed, the
concept that antigen presenting cells raise differential CD8 T cell responses is a highly novel finding which
warrants further investigation to a mechanism which is therapeutically targetable. This is especially important if
one form of CD8 T cell priming in vivo is initiating lethal neurological disease.

## Key facts

- **NIH application ID:** 9994460
- **Project number:** 2R01NS103212-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Aaron J Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,120
- **Award type:** 2
- **Project period:** 2017-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994460

## Citation

> US National Institutes of Health, RePORTER application 9994460, CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions (2R01NS103212-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9994460. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*