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Mycobacteria possess a unique complex cell wall with arabinogalactan (AG) as a critical component. AG has been identified as a virulence factor of Mtb which is recognized by host galectin-9. Here, we demonstrate that galectin-9 directly inhibited mycobacterial growth through AG-binding property of carbohydrate-recognition domain 2. Furthermore, IgG antibodies with AG specificity were detected in the serum of TB patients. Based on the interaction between galectin-9 and AG, we developed a monoclonal antibody (mAb) screening assay and identified AG-specific mAbs which profoundly inhibit Mtb growth. Mechanistically, proteomic profiling and morphological characterizations revealed that AG-specific mAbs regulate AG biosynthesis, thereby inducing cell wall swelling. Thus, direct AG-binding by galectin-9 or antibodies contributes to protection against TB. Our findings pave the way for the rational design of novel immunotherapeutic strategies for TB control.\n                  <\/jats:p>","DOI":"10.7554\/elife.92737","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T07:25:15Z","timestamp":1704785115000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.92737","source":"Crossref","is-referenced-by-count":2,"title":["Cell-autonomous targeting of arabinogalactan by host immune factors inhibits mycobacterial growth"],"prefix":"10.7554","volume":"13","author":[{"given":"Lianhua","family":"Qin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033nbnf69","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine","place":["Shanghai, 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