AXIN1-dependent regulation of lung macrophage MHC-II expression shapes CD4⁺T cell responses during BCG infection.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be the second leading cause of infectious disease-related mortality globally, surpassed only by COVID-19. The Wnt/β-catenin signaling pathway is involved in regulating TB pathogenesis, with AXIN1-a key negative regulator of this pathway-emerging as a potential target for modulating immune responses. Our study explored the function of AXIN1 in TB by examining its expression in peripheral blood mononuclear cells (PBMCs) from TB patients and its effects on macrophage and CD4+T cell functions. We found that AXIN1 expression was significantly downregulated the PBMCs of TB patients and in macrophages infected with Bacillus Calmette-Guérin (BCG). In Tcf/Lef-Gfp transgenic mice intratracheally infected with Mycobacterium bovis BCG, treatment with XAV939 to upregulate AXIN1 expression inhibited Wnt/β-catenin signaling, reduced the proportions of CD4+T cells and macrophages, and decreased the percentage of MHC-II-positive macrophages. Conversely, downregulating AXIN1 in macrophages enhanced CD4+T cell activation and MHC-II-dependent antigen presentation following BCG infection. The accumulated evidence indicates that AXIN1 plays a critical role in modulating macrophage phagocytosis and CD4+T cell reactions because of M. tb infection. Understanding the mechanisms underlying the regulation of the innate-to-adaptive immune transition by AXIN1 could provide new insights into TB pathogenesis and inform the development of novel therapeutic and vaccine strategies.