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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\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag217","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:55:39Z","timestamp":1786121739000},"source":"Crossref","is-referenced-by-count":1,"title":["Sorting nexin 5 deficiency impairs MHC class II antigen presentation and inflammatory responses during tuberculosis"],"prefix":"10.1093","volume":"215","author":[{"given":"Beatriz R S","family":"Dias","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kubra F","family":"Naqvi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria A","family":"Ektnitphong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Alvarez-Arguedas","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn C","family":"Rahlwes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscila C","family":"Campos","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4329-2253","authenticated-orcid":false,"given":"Michael U","family":"Shiloh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]},{"name":"Department of Microbiology, University of Texas Southwestern Medical Center , Dallas, TX,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"2026080712553269900_vkag217-B1","volume-title":"Global tuberculosis report 2025","author":"World Health Organization","year":"2025"},{"key":"2026080712553269900_vkag217-B2","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1001\/jama.1994.03510330076038","article-title":"Efficacy of bcg vaccine in the prevention of tuberculosis. 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