Abstract
The factors governing latency in tuberculosis are not well understood but appear to involve both the pathogen and the host. We have used tuberculin skin test (TST) positivity as a tool to study cytokine responses in latent tuberculosis. To identify the host factors that are important in the maintenance of TST positivity, we examined mycobacteria-specific immune responses of TST-positive (latent tuberculosis) or TST-negative individuals in South India, where TST positivity can define tuberculosis latency. Although purified protein derivative-specific and Mycobacterium tuberculosis culture filtrate antigen-specific Th1 and Th2 cytokines were not statistically significantly different between the 2 groups, the Th17 cytokines (interleukin 17 and interleukin 23) were statistically significantly decreased in TST-positive individuals, compared with those in TST-negative individuals. This Th17 cytokine modulation was associated with statistically significantly increased expression of cytotoxic T lymphocyte antigen 4 (CTLA-4) and Foxp3. Although CTLA-4 blockade failed to restore full production of interleukin 17 and interleukin 23 in TST-positive individuals, depletion of regulatory T cells significantly increased production of these cytokines. TST positivity is characterized by increased activity of regulatory T cells and a coincident down-regulation of the Th17 response.
Highlights
The factors governing latency in tuberculosis are not well understood but appear to involve both the pathogen and the host
Latent tuberculosis is defined as the presence of live M. tuberculosis that persists within an infected host without causing disease
It is characterized by a delayed-type hypersensitivity response to purified protein derivative (PPD) mediated by mycobacteria-specific T cells [4], in areas of low M. tuberculosis transmission, quantiferon assay positivity has been suggested to be a better predictor of latency [5]
Summary
To identify the host factors that are important in the maintenance of TST positivity, we examined mycobacteria-specific immune responses of TST-positive (latent tuberculosis) or TST-negative individuals in South India, where TST positivity can define tuberculosis latency. A positive TST result was defined as an induration at the site of inoculation of at least 12 mm in diameter to account for the high prevalence of environmental mycobacteria. This cutoff was based on a rigorous multivariate analysis of 280,000 patients followed up in South India for 15 years, in which patients with TST indurations of 8–11 mm in reaction to PPD standard had a risk for development of culture-positive tuberculosis that was low (and no different from that of patients with 0–7-mm indurations) but in which patients with indurations of у12 mm, in comparison, had a 3-fold greater relative risk and a 6.l% lifetime risk for development of active tuberculosis [6].
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