# Key sentinel roles of IFN-gamma production by microglia to orchestrate the innate and T cell-mediated protective immunity to prevent reactivation of cerebral Toxoplasma infection

> **NIH NIH R56** · UNIVERSITY OF KENTUCKY · 2020 · $493,173

## Abstract

Reactivation of chronic infection with Toxoplasma gondii in immunocompromised individuals results in the
development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and treatment of
TE, it is critical to define the mechanisms of the protective immunity to control T. gondii in the brain. Our recent
study using bone marrow chimeric mice uncovered that IFN-γ production by brain-resident cells is crucial for
activating the protective innate immunity to limit T. gondii growth and for recruiting and activating immune T
cells in the brain to prevent reactivation of the infection. Our studies also identified that microglia (resident
macrophages in the brain parenchyma) produce IFN-γ in response to T. gondii growth in the brain. These
evidences led us to hypothesize that IFN-γ production by microglia is a key sentinel mechanism of the brain to
provide the early stage innate defense and promptly activate T cell-mediated protective immunity to prevent
reactivation of T. gondii infection. In Aim 1, we will employ mice deficient in IFN-γ only in the microglia among
brain-resident cells and reveal the key sentinel role of microglial IFN-γ to activate the cerebral innate immunity
to limit reactivation of T. gondii infection. We will also determine the role of dense granule protein 6 of T. gondii
as a major target of microglia to detect tachyzoite proliferation in the brain and activate their IFN-γ production.
Aim 2 is to illustrate the crucial protective role of microglial IFN-γ to induce cerebral expression of CXCL9 to
facilitate recruitment of immune T cells into the brain. We will also identify the importance of microglial IFN-γ to
upregulate an expression of MHC class I and II molecules in brain-resident cell populations, which is required
for presenting T. gondii antigens to the T cells recruited into the brain for their activation. In regard to the T cell
population to prevent TE, we previously showed that CD8+ T cells alone in combination with cerebral innate
IFN-γ production are able to prevent reactivation of T. gondii infection. CD8+ T cells recognize target antigens
presented by the MHC class I molecules, and different MHC class I molecules present different antigen
epitopes to CD8+ T cells. Therefore, T. gondii antigens that efficiently activate the protective CD8+ T cells most
likely differ depending on the MHC class I molecules expressed in each individual. There are three MHC class
class I supermotifs, HLA-A2, -A3, and -B7, which encompass 90% of the human population. Aim 3 is to
identify the T. gondii molecules that most efficiently stimulate IFN-γ-producing CD8+ T cells capable of
preventing TE specifically for each of these three MHC class I supermotifs. We will also confirm an efficiency
of the immunization with the identified T. gondii molecules to activate CD8+ T cells capable of preventing TE
using transgenic mice expressing these human MHC molecules. These studies will uncover the critical
cerebral immune system c...

## Key facts

- **NIH application ID:** 10237038
- **Project number:** 1R56AI152597-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** YASUHIRO SUZUKI
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $493,173
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237038

## Citation

> US National Institutes of Health, RePORTER application 10237038, Key sentinel roles of IFN-gamma production by microglia to orchestrate the innate and T cell-mediated protective immunity to prevent reactivation of cerebral Toxoplasma infection (1R56AI152597-01). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10237038. Licensed CC0.

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