TLR1/2-driven macrophage polarization shapes memory CD4+ T-cell responses across the leprosy spectrum

Leprosy presents a clinical-immunological spectrum determined by the host immune response to Mycobacterium leprae. While paucibacillary (PB) patients mount a T_H1-polarized response with effective bacillary control, multibacillary (MB) forms are associated with T_Reg/T_H2 dominance and bacterial persistence. This study investigated the role of Toll-like receptor (TLR) 1/2 expression and signaling in monocyte-derived macrophages, and their influence on memory CD4⁺ T cell polarization across the leprosy spectrum. Peripheral blood mononuclear cells from PB (n = 17), MB (n = 15), and healthy controls (n = 32) were stimulated with M. leprae antigen and analyzed by flow cytometry. PB patients exhibited enhanced TLR1/2 activation, with higher frequencies of IL-12⁺ and IL-1β⁺ macrophages, and increased IL-12 production (measured by mean fluorescence intensity, MFI) compared to MB patients. This robust cytokine response correlated with T_H1-skewed CD4⁺ T cell. In contrast, MB patients displayed impaired TLR1/2 signaling with reduced IL-12/IL-1β and predominant IL-10 production, resulting in a markedly elevated IFN-γ/IL-10 ratio in PB patients. These findings demonstrate that TLR1/2-mediated macrophage activation is associated with adaptive polarisation, with suppressed signalling driving immune deviation in MB patients. The mechanistic link between TLR1/2 dysfunction and the T_H1/Treg balance highlights the IFN-γ/IL-10 ratio as a potential biomarker for clinical stratification and supports TLR1/2 signaling pathways as promising targets for host-directed immunomodulation in leprosy.