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

Area of Science:

• Immunology
• Infectious Diseases
• Molecular Biology

Background:

• Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb).
• CD8+ T cells are crucial for TB immunity but become dysfunctional during infection.
• Impaired CD8+ T cell cytotoxicity and localization limit their effectiveness in TB granulomas.

Purpose of the Study:

• To identify factors regulating CD8+ T cell dysfunction in TB.
• To investigate the role of the nuclear receptor NR4A1 in CD8+ T cell immunity against Mtb.
• To explore the NR4A1-NKG7 axis as a potential therapeutic target for TB.

Main Methods:

• Utilized knockout mice (Nr4a1-/-) and adoptive-transfer models.
• Performed bulk and single-cell RNA sequencing to analyze gene expression.
• Conducted spatial analyses and ChIP-qPCR to assess T cell infiltration and NR4A1 binding.
• Validated findings in macaque and human datasets.
• Tested pharmacologic inhibition of NR4A1 in vivo.

Main Results:

• Nr4a1-/- mice showed reduced Mtb burden, attenuated pathology, and improved CD8+/CD4+ T cell ratios.
• NR4A1 deficiency led to enhanced CD8+ T cell effector functions, including increased cytotoxicity.
• Gene expression analysis revealed suppressed exhaustion pathways and expanded cytotoxic CD8+ T cell subsets (Nkg7+, Granzyme+).
• NR4A1 directly binds to the Nkg7 promoter, regulating its expression.
• Pharmacologic NR4A1 inhibition restored CD8+ T cell function and reduced Mtb load.

Conclusions:

• NR4A1 acts as a key negative regulator of CD8+ T cell immunity in tuberculosis.
• The NR4A1-NKG7 interaction is critical for controlling CD8+ T cell-mediated immunity against Mtb.
• Targeting the NR4A1-NKG7 axis represents a promising host-directed therapeutic strategy for TB.