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

Summary 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)‐γ 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‐γ levels in whole blood supernatants were depressed. A role for CD4 + CD25 + T cells in depressed IFN‐γ production during TB was substantiated in depletion experiments, where CD25 + ‐depleted CD4 T cells produced increased amounts of IFN‐γ upon MTB stimulation compared to unseparated T cells. At follow‐up, IFN‐γ 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‐γ production.