A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis

Active tuberculosis (TB) is associated with prolonged suppression of Mycobacterium tuberculosis (MTB)-specific immune responses, but mechanisms involved are understood incompletely. We investigated a potential role for CD4(+)CD25(+) regulatory T cells in depressed anti-MTB immunity by evaluating serially CD4 cell phenotype and interferon (IFN)-gamma production by mononuclear cells from patients with TB. At diagnosis, frequencies of CD4(+)CD25(+) T cells were increased in blood from TB patients compared to healthy purified protein derivative (PPD)-positive controls (with a history of prior TB exposure), and remained elevated at completion of therapy (6 months). By contrast, expression of another activation marker, CD69, by CD4 T cells was increased at diagnosis, but declined rapidly to control levels with treatment. Among CD4(+)CD25(+) T cells from TB patients at diagnosis those expressing high levels of CD25, probably representing regulatory T cells, were increased 2.9-fold when compared to control subjects, while MTB-stimulated IFN-gamma levels in whole blood supernatants were depressed. A role for CD4(+)CD25(+) T cells in depressed IFN-gamma production during TB was substantiated in depletion experiments, where CD25(+)-depleted CD4 T cells produced increased amounts of IFN-gamma upon MTB stimulation compared to unseparated T cells. At follow-up, IFN-gamma production improved most significantly in blood from TB patients with high baseline frequencies of CD4(+)CD25(+) T cells (more than threefold higher than controls for both total and CD25(hi+) CD4 T cells), who also had a significant drop in frequencies of both total and 'regulatory' CD4(+)CD25(+) T cells in response to treatment. Expansion of CD4(+)CD25(+) regulatory T cells during active TB may play a role in depressed T cell IFN-gamma production.