# Unleashing CD8+ T Cells for TB Defense

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $249,085

## Abstract

PROJECT SUMMARY
This R21 application is based on exciting and novel preliminary data supporting the hypothesis that the
orphan nuclear receptor NR4A1 restrains the protective function of CD8+ T cells in tuberculosis (TB). We
found the NR4A1-/- mice control pulmonary infection with Mycobacterium tuberculosis (Mtb) significantly
better than wildtype (WT) mice. A similar effect was observed in WT mice treated with the NR4A1
antagonist DIM-C. In an adoptive transfer experiment, NR4A1-/- CD8+ T cells protected Rag1-/- mice from
aerosol Mtb infection better than transferred CD8+ T cells from NR4A1-/- or WT donors. This is remarkable
since prior studies found little or no protection from transferred WT CD8+ T cells, which was confirmed in
our experiment. Immunohistochemistry of lung TB lesions showed greater infiltration of CD8+ T cells in
NR4A1-/- mice compared to WT. Analysis of bulk RNA sequencing data from purified lung CD8+ T cells from
Mtb-infected mice identified upregulation of genes linked to cellular infiltrative capacity and cytotoxicity in
NR4A1-/- compared to WT hosts. If true, these findings will advance the field of cellular immunity in TB and
offer translation potential for NR4A1 inhibition as host-directed therapy. Expression of NR4A1 is induced by
T cell receptor signaling, which is the predominant mechanism for regulating its activity. We found that
NR4A1 mRNA is increased in the lungs of Mtb-infected mice, raising the fundamental question whether
NR4A1-regulated T cell tolerance supports a pathogen-permissive environment in TB. The goal of this R21
application is to confirm and extend key findings of the TB phenotyping, adoptive transfer, and DIM-C
treatment experiments, and to enhance these studies with more detailed outcome measures. We also plan
to perform single cell RNA sequencing of lung leukocytes and spatial transcriptomic studies in Mtb-infected
NR4A1-/- and WT mice as a first step towards identifying and prioritizing mechanistic hypotheses on which
to base a future RO1 proposal. Accordingly, we describe a research plan that is feasible to complete within
two years with the deliverables of an initial publication and a competitive RO1 application.

## Key facts

- **NIH application ID:** 10951331
- **Project number:** 1R21AI185410-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Hardy Kornfeld
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,085
- **Award type:** 1
- **Project period:** 2024-06-10 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951331

## Citation

> US National Institutes of Health, RePORTER application 10951331, Unleashing CD8+ T Cells for TB Defense (1R21AI185410-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10951331. Licensed CC0.

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