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

作者：Venkatasubramanian Sambasivan^*; Dhiman Rohan; Paidipally Padmaja; Cheekatla Satyanarayana S; Tripathi Deepak; Welch Elwyn; Tvinnereim Amy R; Jones Brenda; Theodorescu Dan; Barnes Peter F; Vankayalapati Ramakrishna

来源：PLoS Pathogens, 2015, 11(2): UNSP e1004617.

DOI：10.1371/journal.ppat.1004617

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-beta and IFN-gamma. D4GDI inhibited growth of M. tb in MDMs by enhancing production of IL-1 beta, TNF-alpha 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.

• 出版日期2015-2