Neuroimmune Regulation of CD4⁺ T Cell and Macrophage Effector Responses During Mycobacterium tuberculosis Infection

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem aggravated by drug resistance. Effective control of Mtb depends on coordinated innate and adaptive immune responses, with CD4+ T cells and macrophages playing central roles. Noradrenaline (NA), released by the sympathetic nervous system, acts through adrenergic receptors expressed on immune cells, including α2A/α2C (Adra2ac) and β2 (Adrb2). However, their contribution to TB immunopathology remains incompletely understood. Wild-type C57BL/6 (WT), Adra2ac knockout (KO) mice with elevated NA levels, and Adrb2 KO mice were infected with ~800 CFU of Mtb H37Rv-mCherry. After 28 days, bacterial burden and inflammatory responses were assessed by CFU enumeration and flow cytometry. In vitro assays evaluated the effects of Adrb2 signaling on Th1 differentiation and Mtb-infected macrophages. Adrb2 KO mice showed increased splenic bacterial burden compared with WT mice, whereas Adra2ac KO mice exhibited marked immunomodulation, including increased absolute numbers of pulmonary intravascular CD4+ T cells, higher frequencies of ESAT-6-specific CD4+ T cells, and increased proportions of FOXP3+ regulatory T cells and alveolar macrophages. In vitro, β2-adrenergic activation with fenoterol reduced interferon-γ production by Th1 cells. In Mtb-infected macrophages, NA reduced nitrite production and the frequencies of inducible nitric oxide synthase- and MHC class II-positive cells, while increasing Arg1 expression at later time points. Collectively, these findings indicate that adrenergic signaling differentially regulates innate and adaptive immune responses during TB. Elevated NA associated with Adra2ac deficiency appears to favor protection against Mtb and expansion of antigen-specific CD4+ T cells, whereas β2-adrenergic signaling limits the inflammatory activity of Th1 cells and macrophages.