Ex vivo and in vivo evidence that cigarette smoke-exposed T regulatory cells impair host immunity against Mycobacterium tuberculosis

Abstract

IntroductionA strong epidemiologic link exists between cigarette smoke (CS) exposure and susceptibility to tuberculosis (TB). Macrophage and murine studies showed that CS and nicotine impair host-protective immune cells against Mycobacterium tuberculosis (MTB) infection. While CS and nicotine may activate T regulatory cells (Tregs), little is known about how CS may affect these immunosuppressive cells with MTB infection.MethodsWe investigated whether CS-exposed Tregs could exacerbate MTB infection in co-culture with human macrophages and in recipient mice that underwent adoptive transfer of Tregs from donor CS-exposed mice.ResultsWe found that exposure of primary human Tregs to CS extract impaired the ability of unexposed human macrophages to control an MTB infection by inhibiting phagosome-lysosome fusion and autophagosome formation. Neutralizing CTLA-4 on the CS extract-exposed Tregs abrogated the impaired control of MTB infection in the macrophage and Treg co-cultures. In Foxp3+GFP+DTR+ (Thy1.2) mice depleted of endogenous Tregs, adoptive transfer of Tregs from donor CS-exposed B6.PL(Thy1.1) mice with subsequent MTB infection of the Thy1.2 mice resulted in a greater burden of MTB in the lungs and spleens than those that received Tregs from air-exposed mice. Mice that received Tregs from donor CS-exposed mice and infected with MTB had modest but significantly reduced numbers of interleukin-12-positive dendritic cells and interferon-gamma-positive CD4+ T cells in the lungs, and an increased number of total programmed cell death protein-1 (PD-1) positive CD4+ T cells in both the lungs and spleens.DiscussionPrevious studies demonstrated that CS impairs macrophages and host-protective T effector cells in controlling MTB infection. We now show that CS-exposed Tregs can also impair control of MTB in co-culture with macrophages and in a murine model.

Cigarette Smoking as a Risk Factor for Tuberculosis in Adults: Epidemiology and Aspects of Disease Pathogenesis

“…In addition, nicotine induced production of the immunosuppressive cytokine, IL-10, and transforming growth factor-β by regulatory T cells (Tregs), which also contributed to the intracellular survival of M. tuberculosis [ 98 ]. Similar inhibitory effects of cigarette smoke extract-exposed Tregs on phagosome-lysosome and autophagosome formation by M. tuberculosis -infected human macrophages have been recently reported [ 99 ].…”

“…In vitro study involving smoke-exposed murine macrophages and macrophage cell lines depleted of nAChR or exposed to pure nicotine Nicotine-mediated defective autophagosome formation due to inhibition of NFκB and activation of Tregs [98,99] Abbreviations: nAChR-nicotinic acetylcholine receptor; GLUT1-glucose transporter 1; MARCO-macrophage receptor with a collagenous structure; IL-1β-interleukin-1β; NFκB-nuclear factor kappa B; NLRP3 inflammasome-(nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome; miRNA-micro ribonucleic acid; PAMPs-pathogen-associated molecular patterns; STAT3-signal transducer and activation of transcription 3; TLR2-Toll-like receptor 2; Tregs-regulatory T cells.…”