Neutrophilic LGALS2 drives tuberculosis susceptibility by regulating Th2 polarization via the IFN-γ-HLA-II-CD4 axis.

Th1/Th2 immune imbalance constitutes a critical mechanism underlying Mycobacterium tuberculosis (Mtb)-mediated immune evasion. Nevertheless, the specific regulatory mechanism of neutrophils, the pivotal upstream innate immune cells, remains poorly elucidated in this imbalance. This study integrates multi-omics technologies, combines an in vitro primary cell co-culture model and clinical samples for verification, and systematically elucidates the core mechanism by which neutrophils regulate Th1/Th2 immune imbalance in tuberculosis (TB). Our data demonstrate that LGALS2 is highly expressed in neutrophils and serves as a key susceptibility factor facilitating TB development and progression. A remarkable reduction in the Th1/Th2 ratio was observed in TB patients, reflecting disrupted Th1/Th2 immune homeostasis. Suppression of neutrophilic LGALS2 successfully restored the distorted immune balance. Mechanistically, elevated LGALS2 induces Th2 differentiation through the IFN-γ/HLA-II/CD4 axis, whereas loss of LGALS2 enhances TCR-cascade signaling to promote Th1 differentiation. Further epigenetic analysis reveals that the high expression of LGALS2 is attributed to aberrant methylation of its gene promoter. Taken together, this study provides critical mechanistic clues to two longstanding puzzles in TB immunology: the elusive mechanism driving TB-associated Th1/Th2 imbalance and the poorly understood function of innate neutrophils. We uncover a neutrophil-specific epigenetic axis: promoter hypermethylation upregulates LGALS2, which disturbs Th1/Th2 balance through distinct IFN-γ/HLA-CD4 and TCR signaling cascades to heighten TB susceptibility. The findings provide potential novel targets for TB precision immunotherapy.