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bioRxiv · 10.64898/2026.01.12.699051

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

Fatima, S.·Chen, Y.·Smulan, L.·Satish, B.·Jameson, M.·Saini, S.·Johnson, C.·Tay, A.·Shihui, F.·Rahmathulla, H.·Balachander, A.·Howland, S.·Kornfeld, H.·Singhal, A.
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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. A one-sentence summary of your paperNR4A1 suppresses CD8+ T cell infiltration and cytotoxicity in TB lesions, and its inhibition enhances host resistance to Mtb infection.

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Fatima, S., Chen, Y., Smulan, L., Satish, B., Jameson, M., Saini, S., Johnson, C., Tay, A., Shihui, F., Rahmathulla, H., Balachander, A., Howland, S., Kornfeld, H., Singhal, A.. 2026-01-13. NR4A1 limits CD8⁺ T Cell effector responses and protection in tuberculosis. https://doi.org/10.64898/2026.01.12.699051

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