Mycobacterium tuberculosis19-Kilodalton Lipoprotein InhibitsMycobacterium smegmatis-Induced Cytokine Production by Human Macrophages In Vitro

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Abstract
Vaccination of mice withMycobacterium vaccaeorM. smegmatisinduces some protection againstM. tuberculosischallenge. The 19-kDa lipoprotein ofM. tuberculosis, expressed inM. vaccaeorM. smegmatis(M. smeg19kDa), abrogates this protective immunity. To investigate the mechanism of this suppression of immunity, human monocyte-derived macrophages (MDM) were infected withM. smeg19kDa. Infection resulted in reduced production of tumor necrosis factor alpha (TNF-α) (P< 0.01), interleukin-12 (IL-12) (P< 0.05), IL-6 (P< 0.05), and IL-10 (P< 0.05), compared to infection withM. smegmatisvector (M. smegV). Infection withM. smeg19kDa and withM. smegV had no differential effect on expression of costimulatory molecules on MDM, nor did it affect the proliferation of presensitized T cells cocultured with infected MDM. When MDM were infected withM. smegmatisexpressing mutated forms of the 19-kDa lipoprotein, including non-O-glycosylated (M. smeg19NOG), nonsecreted (M. smeg19NS), and nonacylated (M. smeg19NA) variants, the reduced production of TNF-α or IL-12 was not observed. When the purified 19-kDa lipoprotein was added directly to cultures of infected monocytes, there was little effect on either induction of cytokine production or its inhibition. Thus, the immunosuppressive effect is dependent on glycosylated and acylated 19-kDa lipoprotein present in the phagosome containing the mycobacterium. These results suggest that the diminished protection against challenge withM. tuberculosisseen in mice vaccinated withM. smegmatisexpressing the 19-kDa lipoprotein is the result of reduced TNF-α and IL-12 production, possibly leading to reduced induction of T-cell activation.