{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:39:25Z","timestamp":1792651165483,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010721","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T00:00:00Z","timestamp":1659571200000}}],"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE-1752814"],"award-info":[{"award-number":["DGE-1752814"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R01AI143722"],"award-info":[{"award-number":["1R01AI143722"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI063302"],"award-info":[{"award-number":["P01 AI063302"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19 AI106754"],"award-info":[{"award-number":["U19 AI106754"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The prevailing model of protective immunity to tuberculosis is that CD4 T cells produce the cytokine IFN-\u03b3 to activate bactericidal mechanisms in infected macrophages. Although IFN-\u03b3-independent CD4 T cell based control of\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>tuberculosis<\/jats:italic>\n                    infection has been demonstrated\n                    <jats:italic>in vivo<\/jats:italic>\n                    it is unclear whether CD4 T cells are capable of directly activating macrophages to control infection in the absence of IFN-\u03b3. We developed a co-culture model using CD4 T cells isolated from the lungs of infected mice and\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>tuberculosis<\/jats:italic>\n                    -infected murine bone marrow-derived macrophages (BMDMs) to investigate mechanisms of CD4 dependent control of infection. We found that even in the absence of IFN-\u03b3 signaling, CD4 T cells drive macrophage activation, M1 polarization, and control of infection. This IFN-\u03b3-independent control of infection requires activation of the transcription factor HIF-1\u03b1 and a shift to aerobic glycolysis in infected macrophages. While HIF-1\u03b1 activation following IFN-\u03b3 stimulation requires nitric oxide, HIF-1\u03b1-mediated control in the absence of IFN-\u03b3 is nitric oxide-independent, indicating that distinct pathways can activate HIF-1\u03b1 during infection. We show that CD4 T cell-derived GM-CSF is required for IFN-\u03b3-independent control in BMDMs, but that recombinant GM-CSF is insufficient to control infection in BMDMs or alveolar macrophages and does not rescue the absence of control by GM-CSF-deficient T cells. In contrast, recombinant GM-CSF controls infection in peritoneal macrophages, induces lipid droplet biogenesis, and also requires HIF-1\u03b1 for control. These results advance our understanding of CD4 T cell-mediated immunity to\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>tuberculosis<\/jats:italic>\n                    , reveal important differences in immune activation of distinct macrophage types, and outline a novel mechanism for the activation of HIF-1\u03b1. We establish a previously unknown functional link between GM-CSF and HIF-1\u03b1 and provide evidence that CD4 T cell-derived GM-CSF is a potent bactericidal effector.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1010721","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T13:41:41Z","timestamp":1658756501000},"page":"e1010721","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":58,"title":["IFN-\u03b3-independent control of M. tuberculosis requires CD4 T cell-derived GM-CSF and activation of HIF-1\u03b1"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4773-379X","authenticated-orcid":true,"given":"Erik","family":"Van Dis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas M.","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huntly M.","family":"Morrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M.","family":"Fines","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet Peace","family":"Babirye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily H.","family":"McCann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagar","family":"Rawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery S.","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4182-9048","authenticated-orcid":true,"given":"Sarah 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