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Soluble TNFRp75 regulates host protective immunity against Mycobacterium tuberculosis
- Source :
- Journal of Clinical Investigation. April, 2014, Vol. 124 Issue 4, p1537, 15 p.
- Publication Year :
- 2014
-
Abstract
- Development of host protective immunity against Mycobacterium tuberculosis infection is critically dependent on the inflammatory cytokine TNF. TNF signals through 2 receptors, TNFRp55 and TNFRp75; however, the role of TNFRp75-dependent signaling in immune regulation is poorly defined. Here we found that mice lacking TNFRp75 exhibit greater control of M. tuberculosis infection compared with WT mice. [TNFRp75.sup.-/-] mice developed effective bactericidal granulomas and demonstrated increased pulmonary recruitment of activated DCs. Moreover, IL-12p40-dependent migration of DCs to lung draining LNs of infected [TNFRp75.sup.-/-] mice was substantially higher than that observed in WT M. tuberculosis-infected animals and was associated with enhanced frequencies of activated M. tuberculosis-specific IFN-[gamma]-expressing CD4+ T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization ofTNFRp75 in M. tuberculosis-infected WT BM-derived DCs (BMDCs) increased production of bioactive TNF and IL-12p40 to a level equivalent to that produced by [TNFRp75.sup.-/-] BMDCs. Addition of exogenous TNFRp75 to [TNFRp75.sup.-/-] BMDCs infected with M. tuberculosis decreased IL-12p40 synthesis, demonstrating that TNFRp75 shedding regulates DC activation. These data indicate that TNFRp75 shedding downmodulates protective immune function and reduces host resistance and survival; therefore, targeting TNFRp75 may be beneficial for improving disease outcome.<br />Introduction Mycobacterium tuberculosis is a highly efficient intracellular pathogen that requires specific cellular adaptive Thl immune responses for host protection. Successful control of M. tuberculosis relies not only on a [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 124
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.371192284
- Full Text :
- https://doi.org/10.1172/JCI45005