Abstract
In this study, we found that a subpopulation of CD4+CD25+ (85% Foxp3+) cells from persons with latent tuberculosis infection (LTBI) inhibits growth of M. tuberculosis (M. tb) in human monocyte-derived macrophages (MDMs). A soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic CD4+CD25+ (85% Foxp3+) cells is responsible for this inhibition of M. tb growth in human macrophages and in mice. M. tb-expanded CD4+CD25+Foxp3+D4GDI+ cells do not produce IL-10, TGF-β and IFN-γ. D4GDI inhibited growth of M. tb in MDMs by enhancing production of IL-1β, TNF-α and ROS, and by increasing apoptosis of M. tb-infected MDMs. D4GDI was concentrated at the site of disease in tuberculosis patients, with higher levels detected in pleural fluid than in serum. However, in response to M. tb, PBMC from tuberculosis patients produced less D4GDI than PBMC from persons with LTBI. M. tb-expanded CD4+CD25+ (85% Foxp3+) cells and D4GDI induced intracellular M. tb to express the dormancy survival regulator DosR and DosR-dependent genes, suggesting that D4GDI induces a non-replicating state in the pathogen. Our study provides the first evidence that a subpopulation of CD4+CD25+ (85% Foxp3+) cells enhances immunity to M. tb, and that production of D4GDI by this subpopulation inhibits M. tb growth.
Highlights
Tuberculosis (TB) causes an estimated 1.7 million deaths world-wide annually
Most people who are infected with Mycobacterium tuberculosis (M. tb) have latent tuberculosis infection (LTBI) with protective immunity
We found that M. tb-activated CD4+CD25+ (85% Foxp3+) T-cells from individuals with latent tuberculosis infection (LTBI) can inhibit growth of M. tb in human monocyte-derived macrophages (MDMs) through production of Rho GDP dissociation inhibitor (D4GDI), a small GTP-binding protein
Summary
Tuberculosis (TB) causes an estimated 1.7 million deaths world-wide annually. Reducing morbidity and mortality from TB hinges on developing an improved vaccine, which in turn depends on understanding the immune response. T cells play a crucial role in protective immunity against Mycobacterium tuberculosis (M. tb) and other intracellular pathogens [1] in part through production of IFN-γ, which is required for resistance to infection [2]. Uncontrolled T-cell responses can cause tissue damage, which can be reduced by regulatory CD4+ T-cells (Tregs) that express CD25 and Foxp3 [3]. It is generally believed that CD4+CD25+Foxp3+ T-cells inhibit effective immunity to microbial pathogens. Human CD4+CD25+Foxp3+ cells produce TGF-β and IL-10, and inhibit IFN-γ production by CD4+ and CD8+ cells [6], suggesting that they may limit tissue inflammation and destruction. Other studies have found increased number of CD4+Foxp3+ T-cells in TB patients, which inhibit immune responses [6], [8], [9]
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