Sorting nexin 5 mediates antigen presentation and immunity against <i>Mycobacterium tuberculosis</i>

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 <i>Mycobacterium tuberculosis</i> (Mtb) infection are incompletely defined. Sorting nexin 5 (SNX5) is a protein best known for roles in endosomal trafficking, antigen processing, and antiviral host defense, but its contribution to immunity during Mtb infection is unknown. Here, we show that SNX5-deficient mice exhibit markedly increased mortality following low-dose aerosol infection despite unchanged pulmonary bacterial burden compared to wild-type mice. <i>Snx5</i> ^-/- mice developed exacerbated lung inflammation without major alterations in immune cell recruitment. In macrophages, <i>Snx5</i> did not affect phagocytosis, vacuolar maturation, intracellular bacterial control, or global transcriptional responses to Mtb, but was required for efficient MHC class II antigen presentation. <i>Snx5</i> deficiency reduced antigen degradation, limited peptide loading onto MHC-II and impaired activation of antigen-specific CD4⁺ T cells without altering surface MHC-II abundance or expression of costimulatory molecules. Together, these findings identify SNX5 as a previously unrecognized regulator of MHC-II peptide loading that shapes inflammatory outcomes during pulmonary Mtb infection, highlighting a role for the endosomal sorting machinery in immunity to intracellular pathogens.