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Here we reveal that Gram-positive gut-microbiota-derived pathogen-associated molecular patterns promote the CCL2-dependent infiltration of hepatotoxic Ly6C\n                    <jats:sup>hi<\/jats:sup>\n                    monocytes into the APAP-damaged liver, thus inducing APAP-ALI. Conversely, Gram-negative bacterial pathogen-associated molecular patterns activate hepatic CD103\u207a cDC1s to produce IL-15, which in turn expands intrahepatic tissue-resident memory CD8\u207a T (T\n                    <jats:sub>RM<\/jats:sub>\n                    ) cells and promotes protective immunity against APAP-derived liver injury. APAP-ALI was further exacerbated in Batf3-knockout and Rag1-knockout mice owing to an increased population of intrahepatic Ly6C\n                    <jats:sup>hi<\/jats:sup>\n                    monocytes in both knockout strains. The adoptive transfer of hepatic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells or hepatic CD103\n                    <jats:sup>+<\/jats:sup>\n                    cDC1s from wild-type mice ameliorated APAP-ALI in both knockout mice. Notably, CD44\n                    <jats:sup>+<\/jats:sup>\n                    CD69\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>RM<\/jats:sub>\n                    cells within hepatic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, when activated by IL-15\/IL-15R\u03b1 from hepatic CD103\n                    <jats:sup>+<\/jats:sup>\n                    cDC1s of APAP mice, played a crucial role in inducing apoptosis of liver-infiltrating monocytes through direct cell-to-cell interactions and granzyme B secretion. Human results supported these animal findings. Our findings underscore the existence of an intrahepatic protective immune system, the hepatic CD103\n                    <jats:sup>+<\/jats:sup>\n                    cDC1\/CD8\n                    <jats:sup>+<\/jats:sup>\n                    T\n                    <jats:sub>RM<\/jats:sub>\n                    axis, which regulates APAP-ALI by controlling pathogenic monocytes.\n                  <\/jats:p>","DOI":"10.1038\/s12276-025-01565-3","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T05:43:54Z","timestamp":1762494234000},"page":"2458-2474","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery of intrahepatic CD103+ cDC1\/CD8+ TRM protective immune axis against acetaminophen-induced acute liver injury"],"prefix":"10.1038","volume":"57","author":[{"given":"Jinjoo","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong-Ho","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kee-Hyun","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Suk","family":"Cha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JungHyub","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6198-4512","authenticated-orcid":false,"given":"Yoe-Sik","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6210-4927","authenticated-orcid":false,"given":"Seok-Hee","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyoung","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Young","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Chul","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2233-9449","authenticated-orcid":false,"given":"Yong-Soo","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"1565_CR1","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.redox.2016.10.001","volume":"10","author":"K Du","year":"2016","unstructured":"Du, K., Ramachandran, A. & Jaeschke, H. 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