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

During <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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). <i>Mtb</i>-infected <i>Nr4a1</i> ^-/- 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 <i>Nkg7</i> ⁺ and <i>Granzyme</i> ⁺ cytotoxic CD8⁺ T cell subsets in <i>Nr4a1</i> ^-/- mice. Spatial analyses demonstrated increased infiltration of <i>Nkg7</i> ⁺ activated CD8⁺ T cells in <i>Nr4a1</i> ^-/- lesions. ChIP-qPCR showed NR4A1 binding to <i>Nkg7</i> promoter, and <i>Nkg7</i> knockdown abrogated the enhanced cytotoxicity of <i>Nr4a1</i> ^-/- CD8⁺ T cells. Pharmacologic inhibition of NR4A1 reduced <i>Mtb</i> burden and pathology, and restored <i>Nkg7</i> 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.