Whole β-glucan particles modulate BCG-induced macrophage and CD4+ T-cell responses via the Dectin-1-JAK1/STAT1 pathway.

Tuberculosis (TB) remains a major global health burden, and Bacille Calmette-Guérin (BCG) provides inconsistent protection against adult pulmonary disease. Adjuvant strategies to enhance BCG efficacy are urgently needed. Here we show that whole β-glucan particles (WGP) enhance BCG-induced immune responses and improve protection against mycobacterial challenge. In vitro, WGP enhances macrophage functions associated with antigen processing during BCG exposure, including phagocytosis, lysosomal acidification, intracellular degradation, and the upregulation of MHC-II/CD80/CD86. WGP co-exposure partially attenuates the early IL-10 response induced by BCG. Mechanistically, whole β-glucan particles activate the Dectin-1-JAK1-STAT1 pathway, and disruption of this axis reduces MHC-II upregulation and impairs macrophage-supported OT-II CD4+ T-cell proliferation and IFN-γ production. In vivo, using female wild-type and Dectin-1 knockout C57BL/6 J mice, we find that split-site administration of WGP and BCG is better tolerated than same-site mixing and is associated with a less inflammatory early pulmonary myeloid profile. Under this optimized regimen, WGP plus BCG enhances CD4+ memory-associated responses and improves bacterial control while reducing lung inflammation in a Mycobacterium tuberculosis H37Ra challenge model. These findings support further evaluation of WGP as an adjunct candidate for BCG-based vaccination strategies and may inform the development of improved tuberculosis vaccines.