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

PLoS Pathogens

Peter F. Barnes¹  Satyanarayana S. Cheekatla¹  Padmaja Paidipally¹  Elwyn Welch¹  Ramakrishna Vankayalapati¹  Amy R. Tvinnereim¹  Deepak Tripathi¹  Sambasivan Venkatasubramanian¹  Rohan Dhiman¹  Brenda Jones²  Dan Theodorescu³ 

[1] Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Center, Tyler, Texas, United States of America;Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America;University of Colorado Comprehensive Cancer Center, Aurora, Colorado, United States of America

关键词: Mycobacterium tuberculosis;    Tuberculosis;    Apoptosis;    Macrophages;    Small interfering RNAs;    T cells;    Flow cytometry;    Monocytes;   

DOI  :  10.1371/journal.ppat.1004617

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY