NR4A1 limits CD8T Cell effector responses and protection in tuberculosis.

During() infection, CD8T 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 CD8T cell immunity in tuberculosis (TB).-infectedmice displayed reduced bacterial burden, attenuated pathology, higher lung CD8/CD4T cell ratios, and enhanced CD8T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion ofandcytotoxic CD8T cell subsets inmice. Spatial analyses demonstrated increased infiltration ofactivated CD8T cells inlesions. ChIP-qPCR showed NR4A1 binding topromoter, andknockdown abrogated the enhanced cytotoxicity ofCD8T cells. Pharmacologic inhibition of NR4A1 reducedburden and pathology, and restoredexpression and CD8T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8T cell-mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target.