# CD4 dysfunction and cerebral toxoplasmosis

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2023 · $598,186

## Abstract

Abstract
Latent toxoplasmosis continues to be a problem for immunocompromised infected
individuals and toxoplasmic encephalitis (TE) is one of the most common life threatening
central nervous system infections in these patients. The reactivation of latent
toxoplasmosis is attributed to lack of adequate CD4 T cell help that compromises the CD8
T cell immunity against the parasite. Similar to humans, mouse models of toxoplasmosis
have demonstrated the critical role of CD4 T cells for the maintenance of robust CD8 T
cell immunity. In a recent study we demonstrated that CD8 T dysfunction leading to
reactivation in chronically infected host is a consequence of CD4 T cell exhaustion.
Treatment of chronic host with antigen-specific non-exhausted CD4 T cells can restore
CD8 T cell functionality and prevent reactivation. Interestingly, CD4 exhaustion is linked
to up-regulation of transcription factor BLIMP-1, which causes an increase in the
expression of inhibitory receptors on these cells. Preliminary data for the proposal
suggests that during latent toxoplasmosis increased BLIMP-1 expression leads to
epigenetic changes in antigen-specific, CD4 TCM (central memory) subset. The
transcription factor gains accessibility to chromatin sites on this population and changes
their epigenetic landscape. BLIMP-1 ablation re-invigorates CD4 T cells due to
downregulation of inhibitory receptors and increased expression of positive co-stimulatory
molecules. The proposal has two specific aims. In aim 1 we will determine the chromatin
accessible sites on CD4 TCM that BLIMP-1 binds to. We plan to define the epigenetic
changes in CD4 TCM during latent toxoplasmosis that leads to their exhaustion. In aim 2
studies will be performed to evaluate if restoration of CD4 T cell function due to BLIMP-1
ablation is dependent on the up-regulation of 4-1BB and OX40 or other costimulatory
molecules identified in aim 1. We will determine if cell intrinsic signaling by these co-
stimulatory molecules is required for optimal recovery of CD4 T cell function in BLIMP-1
ablated cells. Finally, studies will be performed to determine if CD4 T cells treated with
agonist for co-stimulatory molecules downregulate inhibitory receptors on CD8 population
and confer strong effector cytotoxic program on these cells that is critical for containing
chronic toxoplasma infection.

## Key facts

- **NIH application ID:** 10403626
- **Project number:** 5R01AI153108-03
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** IMTIAZ AHMED KHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $598,186
- **Award type:** 5
- **Project period:** 2020-06-16 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403626

## Citation

> US National Institutes of Health, RePORTER application 10403626, CD4 dysfunction and cerebral toxoplasmosis (5R01AI153108-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10403626. Licensed CC0.

---

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