{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T18:56:37Z","timestamp":1779216997539,"version":"3.51.4"},"posted":{"date-parts":[[2025,5,13]]},"group-title":"Immunology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["NIH P01 AI063302"],"award-info":[{"award-number":["NIH P01 AI063302"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","award":["NIH 1R01AI113270-01A1"],"award-info":[{"award-number":["NIH 1R01AI113270-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-\u03b3\u2013producing Th1 CD4+ T cells are necessary but insufficient for protection against infection. In humans, the development of IL-17A producing Th17 T cells correlates with protection, however not all individuals develop a Th17 response. In mice, experimental vaccines can elicit protective Th17 cells, yet Th17s are rare in primary infection. Why Mtb fails to consistently elicit Th17s is unknown. Here, we identify factors suppressing Th17 responses during primary infection. We demonstrate that the lack of Th17 induction is independent of route and duration. Next, using\n                  <jats:italic>Tbet<\/jats:italic>\n                  deficient mice, we show that Mtb drives a Th1 response that is only partially protective and limits Th17 cell production in an IFN-\u03b3 independent manner. We further reveal that the ESX-1 type VII secretion system and lipid PDIM suppresses Th17 responses. Infection with ESX-1 or PDIM mutants results in significantly increased Th17 T cells and IL-17A cytokine in the lungs, and infection of IL-17A deficient animals partially restores virulence of ESX-1 and PDIM mutants. Although the ESX-1 secretion system and lipid PDIM elicits type I IFN, which can suppress Th17 differentiation, we find that suppression of Th17 is independent of type I IFN. Instead, ESX-1 and PDIM suppresses production of IL-23, a cytokine that promotes Th17 differentiation, in dendritic cells found in mediastinal lymph nodes during Mtb infection. These findings define a new function of the ESX-1 secretion system and PDIM in Mtb virulence, a long-standing question in tuberculosis research.\n                <\/jats:p>","DOI":"10.1101\/2025.05.08.652811","type":"posted-content","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T19:00:17Z","timestamp":1747162817000},"source":"Crossref","is-referenced-by-count":3,"title":["<i>Mycobacterium tuberculosis<\/i>\n                  suppresses protective Th17 responses during infection"],"prefix":"10.64898","author":[{"given":"Alex","family":"Zilinskas","sequence":"first","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Balakhmet","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas","family":"Fox","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heyuan Michael","family":"Ni","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Agudelo","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helia","family":"Samani","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4182-9048","authenticated-orcid":false,"given":"Sarah A.","family":"Stanley","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA"},{"name":"Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051302400743000_2025.05.08.652811v4.1","unstructured":"World Health Organization, Global Tuberculosis Report 2022. 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