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

Abstract

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.

Figure 1

Gene networks, immune response, and bacteremia. Early and prolonged up-regulation of immune gene networks correlated with the development of vaccine-elicited T cell responses and anti–bacille Calmette-Guérin (BCG) immunity after BCG vaccination. The mean levels of expression of individual gene networks were plotted over the levels of purified protein derivative (PPD)–specific interferon (IFN)–γ–producing T cells and BCG colony-forming units at each time point after BCG vaccination/infection. The mean expression levels of individual gene networks were calculated as the means of fold changes in the expression of selected genes in each of the gene networks (i.e., the mean for a gene network is the total of the means of fold changes for the up-regulated genes divided by the no. of the up-regulated genes). The levels of BCG colony-forming units in simian immunodeficiency virus–infected monkeys were persistent and were higher than those in healthy naive monkeys [14]. Network (i) is the gene network of lymphokines and lymphokine receptors for immune activation/adaptive T cell responses; network (ii) is the gene network of chemokines and chemokine receptors for mucosal/tissue migration and T cell activation; network (iii) is the gene network of signal costimulators for vaccine-elicited T cell responses; network (iv) is the gene network of transcription and trans-activation; network (v) is the gene network of T helper commitments; network (vi) is the gene network of cytotoxic effectors; and network (vii) is the gene network of innate and other immune factors (see the first section of Results). PBMCs, peripheral-blood mononuclear cells.