<i>In vitro</i>restoration of T cell responses in tuberculosis and augmentation of monocyte effector function against<i>Mycobacterium tuberculosis</i>by natural inhibitors of transforming growth factor β

Memory T cells are critical for the control of intracellular pathogens and require few signals for maintenance; however, erosion of established preexisting memory CD8+ T cells has been shown to occur during infection with heterologous viral infections. We evaluated whether this also occurs during infection with various intracellular bacteria and what mechanisms may be involved. We demonstrate that erosion of established memory is also induced during infection of mice with various intracellular bacteria, such as Listeria monocytogenes, Salmonella typhimurium, and Mycobacterium bovis (bacillus Calmette-Guérin). The extent of erosion of established CD8+ T cell memory was dependent on the virulence of the heterologous pathogen, not persistence. Furthermore, when antibiotics were used to comprehensively eliminate the heterologous pathogen, the numbers of memory CD8+ T cells were not restored, indicating that erosion of preexisting memory CD8+ T cells was irreversible. Irrespective of the initial numbers of memory CD8+ T cells, challenge with the heterologous pathogen resulted in a similar extent of erosion of memory CD8+ T cells, suggesting that cellular competition was not responsible for erosion. After challenge with the heterologous pathogen, effector memory CD8+ T cells were rapidly eliminated. More importantly, erosion of preexisting memory CD8+ T cells was abrogated in the absence of IFN-γ. These studies help reveal the paradoxical role of IFN-γ. Although IFN-γ promotes the control of intracellular bacterial replication during primary infection, this comes at the expense of erosion of preexisting memory CD8+ T cells in the wake of infection with heterologous pathogens.

Section: Discussionmentioning

confidence: 54%

IFN-γ Induces the Erosion of Preexisting CD8 T Cell Memory during Infection with a Heterologous Intracellular Bacterium

Dudani

Krishnan

Sad

2008

“…In other studies, bone marrow or peritoneal derived M infected with live or killed M. tuberculosis or transfected with mycobacterial genes were used as stimulators in CD8 ϩ T cells cultures. However, infected M might not be well suited for this role because they can be suppressive (40,41). In our hands, bone marrow-derived M. tuberculosis-infected M were poor at stimulating mycobacteria-specific proliferation of splenocytes 4 or IFN-␥ production from lung CD4 or CD8 ϩ T cells (14) from infected mice.…”

Section: T Cells and Cd69mentioning

confidence: 84%

CD8+ CTL from Lungs ofMycobacterium tuberculosis-Infected Mice Express Perforin In Vivo and Lyse Infected Macrophages

Serbina¹,

Liu

Scanga³

et al. 2000

146

112

CD8+ T lymphocytes have been implicated in the protective immune response against human and murine tuberculosis. However, the functional role that this cell subset plays during the resolution of infection remains controversial. In this study, we demonstrate the presence of Mycobacterium tuberculosis-specific CD8+ CTL in the lungs and lung-draining lymph nodes of mice infected with M. tuberculosis via the aerosol or i.v. route. These cells expressed perforin in vivo and specifically recognized and lysed M. tuberculosis-infected macrophages in a perforin-dependent manner after a short period of in vitro restimulation. The efficiency of lysis of infected macrophages was dependent upon the time allowed for interaction between macrophage and M. tuberculosis bacilli. Recognition of infected targets by CD8+ CTL was β2-microglobulin and MHC class I dependent and was not CD1d restricted. The presented data indicate that CD8+ T cells contribute to the protective immune response during M. tuberculosis infection by exerting cytotoxic function and lysing infected macrophages.

“…Sustained secretion of IL-10 and TGF-␤ has been reported to result in a long-lasting hyporesponsive (anergic) state to specific Ags (45,46) and is likely in play because PBMC from pulmonary TB patients manifest bioresponses similar to those induced by IL-10 and/or TGF-␤ (12,48,50,51). The increased levels of serum IL-10 and TGF-␤ detected in TB patients, and the increased in vitro IL-10 and TGF-␤ secretion by the PBMC and/or monocytes of TB patients in response to M. tuberculosis Ags, also support a role for these two immune suppressive mediators (7,(52)(53)(54). The fact that M. tuberculosis can directly induce macrophage IL-10 and TGF-␤ production (36,55) and that the growth restriction of M. tuberculosis by human monocytes/macrophages is correlated inversely with the amount of stimulated IL-10 and TGF-␤ secretion (36,56) further underscores their antagonistic role in microbicidal activity in TB.…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis Is Associated with a Down-Modulatory Lung Immune Response That Impairs Th1-Type Immunity

Almeida

Lago

Boéchat

et al. 2009

135

118

Immune mediators associated with human tuberculosis (TB) remain poorly defined. This study quantified levels of lung immune mediator gene expression at the time of diagnosis and during anti-TB treatment using cells obtained by induced sputum. Upon comparison to patients with other infectious lung diseases and volunteers, active pulmonary TB cases expressed significantly higher levels of mediators that counteract Th1-type and innate immunity. Despite the concomitant heightened levels of Th1-type mediators, immune activation may be rendered ineffectual by high levels of intracellular (SOCS and IRAK-M) and extracellular (IL-10 and TGF-βRII, IL-1Rn, and IDO) immune suppressive mediators. These modulators are a direct response to Mycobacterium tuberculosis as, by day 30 of anti-TB treatment, many suppressive factors declined to that of controls whereas most Th1-type and innate immune mediators rose above pretreatment levels. Challenge of human immune cells with M. tuberculosis in vitro up-regulated these immune modulators as well. The observed low levels of NO synthase-2 produced by alveolar macrophages at TB diagnosis, along with the heightened amounts of suppressive mediators, support the conclusion that M. tuberculosis actively promotes down-modulatory mediators to counteract Th1-type and innate immunity as an immunopathological strategy. Our data highlight the potential application of immune mediators as surrogate markers for TB diagnosis or treatment response.