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–/– 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–/– 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-γ–expressing CD4+ T cells. In WT mice, TNFRp75 shedding correlated with markedly reduced bioactive TNF levels and IL-12p40 expression. Neutralization of TNFRp75 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–/– BMDCs. Addition of exogenous TNFRp75 to TNFRp75–/– 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.
Roanne Keeton, Nasiema Allie, Ivy Dambuza, Brian Abel, Nai-Jen Hsu, Boipelo Sebesho, Philippa Randall, Patricia Burger, Elizabeth Fick, Valerie F.J. Quesniaux, Bernhard Ryffel, Muazzam Jacobs
(A and B) WT and TNFRp75–/– BMDCs were infected with M. tuberculosis at an MOI of 5:1, and TNFRp75 surface expression (A) and soluble TNFRp55 (B) were measured. Data (mean ± SEM of quadruplicate experiments) are representative of 1 of 2 experiments. (C–E) WT, TNFRp75–/–, and TNFRp55–/– mice were infected with 50–100 CFU M. tuberculosis. Surface TNFRp75 (C) was measured by flow cytometry in BAL cells, and soluble TNFRp55 (D) and TNFRp75 (E) were measured in lung homogenates by ELISA. ND, not detectable. Data (mean ± SEM of 4–5 mice per group) are representative of 1 of 2 similar experiments. *P < 0.05, **P < 0.01, ANOVA.