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

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.