A Rho GDP dissociation inhibitor produced by apoptotic T cells inhibits growth of Mycobacterium tuberculosis (INC2P.415)

Abstract In the current study, we found that a subpopulation of apoptotic T-cells (CD4+CD25+ and 85% Foxp3+) from persons with latent tuberculosis (TB) infection, inhibits growth of M. tuberculosis (M. tb) in human monocyte-derived macrophages (MDMs) from 16.5 ± 1.2 x 106 vs 2.2 ± 1.1 x 106 CFU (p=0.001). Analysis of culture supernatants from T-cells by 2D gel electrophoresis and LC MS/MS indicated that a soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic T-cells is responsible for this inhibition of M.tb growth in MDMs 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 from 10.4 ± 1.1 x 106 vs 2.8 ± 0.6 x 106 CFU (p<0.001) and D4GDI siRNA reversed T-cells-dependent M. tb growth inhibition in MDMs from 1.8 ± 0.3 x 106 to 5.5 ± 1 x 106 CFU (p=0.001). D4GDI enhanced production of IL-1β (43 ± 33 to 193 ± 104 pg/ml, p=0.02), TNF-α (88 ± 126 to 129 ± 111 pg/ml, p=0.03) and ROS production and enhanced apoptosis of M. tb-infected MDMs to inhibit M.tb growth. D4GDI was concentrated at the site of disease in TB patients, with higher levels detected in pleural fluid than in serum. However, in response to M. tb, PBMC from TB patients produced less D4GDI than PBMC from persons with LTBI (13.7 ± 9.3 vs. 40.6 ± 3.2, p=0.02). Our study provides the first evidence that a subpopulation of T-cells enhances immunity to M. tb, and that production of D4GDI by this subpopulation inhibits M. tb growth.