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

Area of Science:

• Immunology
• Molecular Biology
• Infectious Diseases

Background:

• Tuberculosis (TB) infection impairs CD8+ T cell function, limiting their effectiveness against Mycobacterium tuberculosis (Mtb).
• CD8+ T cells show reduced cytotoxicity and poor infiltration into TB granuloma cores.

Purpose of the Study:

• To identify key regulators of CD8+ T cell dysfunction during Mtb infection.
• To investigate the role of nuclear receptor NR4A1 in controlling CD8+ T cell responses in TB.
• To explore the therapeutic potential of targeting the NR4A1-NKG7 axis.

Main Methods:

• Utilized knockout mice (Nr4a1-/-), adoptive-transfer models, and analyzed macaque and human datasets.
• Performed bulk and single-cell RNA sequencing to assess gene expression changes.
• Conducted spatial analyses and ChIP-qPCR to determine NR4A1 binding and its effect on gene promoters.
• Investigated the effects of pharmacologic NR4A1 inhibition.

Main Results:

• Nr4a1-/- mice exhibited reduced Mtb burden, attenuated pathology, and enhanced CD8+ T cell effector functions.
• NR4A1 deficiency led to suppressed gene expression associated with T cell exhaustion and expanded cytotoxic CD8+ T cell subsets (Nkg7+, Granzyme+).
• NR4A1 directly binds to the Nkg7 promoter, and its inhibition restored Nkg7 expression and CD8+ T cell infiltration in Mtb-infected lungs.

Conclusions:

• NR4A1 acts as a critical negative regulator of CD8+ T cell-mediated immunity in TB.
• The NR4A1-NKG7 signaling pathway is a promising target for host-directed therapies against TB.
• Pharmacologic inhibition of NR4A1 demonstrates therapeutic potential for enhancing host resistance to Mtb infection.