Tuberculosis presents a global health challenge and tumor necrosis factor (TNF) signaling is required for host immunity against Mycobacterium tuberculosis (Mtb). 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 /p75  murine strain on host protection during a low-dose aerosol Mtb H37Rv challenge. We report that the presence of membrane-bound TNFRp55 alone in the absence of TNFRp75, results in superior control of a primary Mtb infection where p55 /p75  hyperactive dendritic cells displayed an increased capacity to induce a hyperactive Mtb-specific CD4  T cell response. p55 /p75  dendritic cells expressed a higher frequency of MHCII and increased MFI’s for both CD86 and MHCII, while CD4  T cells had higher expression of CD44 and IFNγ. Next the relative contributions of soluble TNFRp55 and soluble TNFRp75 to host protection against either primary Mtb infection, or during reactivation of latent tuberculosis was delineated by comparing the experimental outcomes of control C57BL/6 mice to transgenic p55 /p75 , p55  and p75  mouse strains. We found that soluble TNFRp55 is redundant for immune regulation during the chronic stages of a primary Mtb infection. However, TNFRp55 together with soluble TNFRp75 have a crucial role in immune regulation of reactivation of latent tuberculosis.
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