# NR4A1 limits CD8+ T Cell effector responses and protection in tuberculosis

## TL;DR

NR4A1 limits CD8+ T cell function in tuberculosis, and blocking it improves immune response and reduces infection.

## Contribution

NR4A1 is identified as a novel negative regulator of CD8+ T cell immunity in TB, with therapeutic potential via the NR4A1-NKG7 axis.

## Key findings

- Mtb-infected Nr4a1−/− mice showed reduced bacterial burden and enhanced CD8+ T cell effector functions.
- NR4A1 binds to the Nkg7 promoter, and Nkg7 knockdown abrogates enhanced cytotoxicity in Nr4a1−/− CD8+ T cells.
- Pharmacologic NR4A1 inhibition reduces Mtb burden and restores CD8+ T cell infiltration and Nkg7 expression.

## Abstract

During Mycobacterium tuberculosis (Mtb) infection, CD8+ T cells exhibit dysfunction with impaired cytotoxicity and limited localization to granuloma cores. Using knockout mice, adoptive-transfer models and validation in macaque and human datasets, we identified the nuclear receptor NR4A1 as a key restrainer of CD8+ T cell immunity in tuberculosis (TB). Mtb-infected Nr4a1−/− mice displayed reduced bacterial burden, attenuated pathology, higher lung CD8+/CD4+ T cell ratios, and enhanced CD8+ T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion of Nkg7+ and Granzyme+ cytotoxic CD8+ T cell subsets in Nr4a1−/− mice. Spatial analyses demonstrated increased infiltration of Nkg7+ activated CD8+ T cells in Nr4a1−/− lesions. ChIP-qPCR showed NR4A1 binding to Nkg7 promoter, and Nkg7 knockdown abrogated the enhanced cytotoxicity of Nr4a1−/− CD8+ T cells. Pharmacologic inhibition of NR4A1 reduced Mtb burden and pathology, and restored Nkg7 expression and CD8+ T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8+ T cell–mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target.

NR4A1 suppresses CD8+ T cell infiltration and cytotoxicity in TB lesions, and its inhibition enhances host resistance to Mtb infection.