Sorting nexin 5 deficiency impairs MHC class II antigen presentation and inflammatory responses during tuberculosis

Tuberculosis (TB) remains one of the leading causes of death from a single infectious agent worldwide, yet the host pathways that regulate antigen presentation and lung inflammation during Mycobacterium tuberculosis (Mtb) infection are incompletely defined. Sorting nexin 5 (SNX5) is a protein implicated in endosomal trafficking, antigen processing, and antiviral host defense, but its contribution to antibacterial immunity is unknown. Here, we show that SNX5-deficient mice exhibit increased mortality following low-dose aerosol Mtb infection despite unchanged pulmonary bacterial burden compared with wild-type mice. Snx5-/- mice developed exacerbated lung inflammation without major alterations in immune cell recruitment. In macrophages, Snx5 did not affect phagocytosis, vacuolar maturation, intracellular bacterial control, or global transcriptional responses to Mtb but was required for efficient major histocompatibility complex (MHC) class II antigen presentation. Snx5 deficiency was associated with reduced endolysosomal proteolysis and impaired MHC class II antigen presentation in vitro, resulting in reduced activation of antigen-specific CD4+ T cells without altering surface MHC class II abundance or costimulatory molecule expression. Together, these findings identify SNX5 as a regulator of MHC class II antigen presentation that influences inflammatory outcomes during pulmonary Mtb infection.