Immune gene networks of mycobacterial vaccine-elicited cellular responses and immunity.

Gene networks of protective lymphocytes after immune activation with live attenuated vaccines remain poorly characterized. Because Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine can confer protection against fatal forms of tuberculosis in humans and monkeys, we made use of macaque models to optimally study immune gene networks after BCG vaccination/infection. We first established and validated a large-scale real-time quantitation system and then used it to measure expression levels of 138 immune genes after BCG vaccination/infection of rhesus macaques. Systemic BCG vaccination induced up to 600-fold increases in expression of 78 immune genes among the 138 genes tested at the time when BCG-elicited T cell responses and immunity were apparent. These up-regulated transcripts constituted multiple gene networks that were linked to various aspects of immune function. Surprisingly, the up-regulation of most of these immune genes in the gene networks occurred at 1 week and was sustained at > or = 6 weeks after BCG vaccination/infection. Although early activation of immune gene networks was an immune correlate of anti-BCG immunity, prolonged up-regulation of these networks coincided with the development of vaccine-elicited T cell responses after BCG vaccination/infection. These findings provide molecular evidence suggesting that the BCG-induced gene networks may represent global transcriptomes and proteomes underlying the development of T cell responses and, ultimately, immunity to mycobacteria.

Adaptive immune response of Vgamma2Vdelta2+ T cells during mycobacterial infections.

To examine the role of T cell receptor (TCR) in gammadelta T cells in adaptive immunity, a macaque model was used to follow Vgamma2Vdelta2+ T cell responses to mycobacterial infections. These phosphoantigen-specific gammadelta T cells displayed major expansion during Mycobacterium bovis Bacille Calmette-Guérin (BCG) infection and a clear memory-type response after BCG reinfection. Primary and recall expansions of Vgamma2Vdelta2+ T cells were also seen during Mycobacterium tuberculosis infection of naive and BCG-vaccinated macaques, respectively. This capacity to rapidly expand coincided with a clearance of BCG bacteremia and immunity to fatal tuberculosis in BCG-vaccinated macaques. Thus, Vgamma2Vdelta2+ T cells may contribute to adaptive immunity to mycobacterial infections.

Induction of an AIDS virus-related tuberculosis-like disease in macaques: a model of simian immunodeficiency virus- mycobacterium coinfection.

The mechanism by which human immunodeficiency virus (HIV)-Mycobacterium tuberculosis coinfection facilitates development of HIV-related tuberculosis is poorly characterized. Macaque models of simian immunodeficiency virus (SIV(mac))-Mycobacterium bovis BCG coinfection were employed to explore the pathogenesis of AIDS virus-related tuberculosis. Following BCG coinfection, SIV (SIV)-infected macaques with high viral loads developed an SIV-related tuberculosis-like disease. This disease was characterized clinically by a syndrome of diarrhea, anorexia, weight loss, and altered levels of consciousness and pathologically by the presence of disseminated granulomas. In contrast, SIV(mac)-infected macaques with low viral loads either showed no evidence of BCG-induced disease or developed focal granulomatous lesions. Pathogenic SIV-BCG interactions appeared to play a critical role in triggering the development of this SIV-related tuberculosis-like disease. BCG coinfection enhanced the destruction of CD4(+) T cells in SIV(mac)-infected macaques whose viral loads were high. Reciprocally, exacerbations of SIV disease led to marked suppression of BCG-specific T-cell responses, persistence of the BCG infection, and development of an SIV-related tuberculosis-like disease. Furthermore, development of this SIV-related tuberculosis-like disease was also seen in naïve macaques simultaneously inoculated with SIV(mac) and BCG. These results provide in vivo evidence that coinfection of AIDS virus-infected individuals with an avirulent mycobacterium can lead to development of a tuberculosis-like disease.