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TNF receptor shedding, however, compromises effective immunity by reducing bioactive TNF through the formation of inactive complexes. In this study, we first compared the effect of total soluble TNF receptors using a transgenic p55<jats:sup>\u0394NS<\/jats:sup>\/p75<jats:sup>\u2212\/\u2212<\/jats:sup> murine strain on host protection during a low\u2010dose aerosol <jats:italic>Mtb<\/jats:italic> H37Rv challenge. We report that the presence of membrane\u2010bound TNFRp55 alone in the absence of TNFRp75 results in superior control of a primary <jats:italic>Mtb<\/jats:italic> infection where p55<jats:sup>\u0394NS<\/jats:sup>\/p75<jats:sup>\u2212\/\u2212<\/jats:sup> hyperactive dendritic cells displayed an increased capacity to induce a hyperactive <jats:italic>Mtb<\/jats:italic>\u2010specific CD4<jats:sup>+<\/jats:sup> T\u2010cell response. p55<jats:sup>\u0394NS<\/jats:sup>\/p75<jats:sup>\u2212\/\u2212<\/jats:sup> dendritic cells expressed a higher frequency of MHCII and increased MFIs for both CD86 and MHCII, while CD4<jats:sup>+<\/jats:sup> T cells had higher expression of CD44 and IFN\u2010\u03b3. Next, the relative contributions of soluble TNFRp55 and soluble TNFRp75 to host protection against either primary Mtb infection or during reactivation of latent tuberculosis were delineated by comparing the experimental outcomes of control C57BL\/6 mice to transgenic p55<jats:sup>\u0394NS<\/jats:sup>\/p75<jats:sup>\u2212\/\u2212<\/jats:sup>, p55<jats:sup>\u0394NS<\/jats:sup> and p75<jats:sup>\u2212\/\u2212<\/jats:sup> mouse strains. We found that soluble TNFRp55 is redundant for immune regulation during the chronic stages of a primary <jats:italic>Mtb<\/jats:italic> infection. However, TNFRp55 together with soluble TNFRp75 has a crucial role in immune regulation of reactivation of latent tuberculosis.<\/jats:p>","DOI":"10.1111\/imm.13385","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T18:44:36Z","timestamp":1623782676000},"page":"524-540","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Immune control of <i>Mycobacterium tuberculosis<\/i> is dependent on both soluble TNFRp55 and soluble TNFRp75"],"prefix":"10.1111","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4808-9756","authenticated-orcid":false,"given":"Roanne","family":"Keeton","sequence":"first","affiliation":[{"name":"Division of Immunology Department of Pathology and Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences University of Cape Town Observatory South 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