A Rho GDP Dissociation Inhibitor Produced by Apoptotic T-Cells Inhibits Growth of Mycobacterium tuberculosis

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.
Author Summary Most people who are infected with Mycobacterium tuberculosis (M. tb) have latent tuberculosis infection (LTBI) with protective immunity. Patients with active tuberculosis have severe disease and ineffective immunity. Understanding how LTBI individuals control infection without developing disease provides important insight into the mechanisms of protective immunity against tuberculosis, and this information is essential for development of an effective vaccine. It is known that a lymphocyte population called T-cells contributes significantly to protective immunity against tuberculosis infection. In the current study, using human and murine models of M. tb infection, we found that a soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by a subpopulation of T-cells (CD4+CD25+Foxp3+) inhibits M. tb growth. We also found that D4GDI induces M. tb genes that are expressed during the non-replicative state. Our results suggest that D4GDI has a previously undescribed positive effect on immunity by enhancing host antimicrobial activity. These findings also may aid in understanding the factors that induce LTBI. Further, this information will facilitate development of improved vaccines and immunotherapeutic strategies to prevent and treat tuberculosis, respectively.