Cutting Edge: Regulatory T Cells Prevent Efficient Clearance of <i>Mycobacterium tuberculosis</i>

Kursar, Mischo; Koch, Markus; Mittrücker, Hans‐Willi; Nouailles, Geraldine; Bonhagen, Kerstin; Kamradt, Thomas; Kaufmann, Stefan H. E.

doi:10.4049/jimmunol.178.5.2661

Cited by 248 publications

(198 citation statements)

References 25 publications

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“…Recent studies found that Tregs proliferate and accumulate at sites of infection [25], and prevent efficient clearance of infection in mice infected with M. tuberculosis [26]. In tuberculosis patients, T cell production of IFN-c in response to mycobacterial Ag is reduced, compared to findings in healthy tuberculin reactors [24].…”

Section: Increased Percentages Of Tregs In Tuberculosis Patientsmentioning

confidence: 99%

Mannose‐capped lipoarabinomannan‐ and prostaglandin E2‐dependent expansion of regulatory T cells in human Mycobacterium tuberculosis infection

et al. 2008

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We evaluated the role of regulatory T cells (CD4 + CD25 + Foxp3 + cells, Tregs) in human Mycobacterium tuberculosis infection. Tregs were expanded in response to M. tuberculosis in healthy tuberculin reactors, but not in tuberculin-negative individuals. The M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) resulted in regulatory T cell expansion, whereas the M. tuberculosis 19-kDa protein and heat shock protein 65 had no effect. Anti-IL-10 and anti-TGF-b alone or in combination, did not reduce expansion of Tregs. In contrast, the cyclooxygenase enzyme-2 inhibitor NS398 significantly inhibited expansion of Tregs, indicating that prostaglandin E2 (PGE2) contributes to Treg expansion. Monocytes produced PGE2 upon culturing with heat-killed M. tuberculosis or ManLAM, and T cells from healthy tuberculin reactors enhanced PGE2 production by monocytes. Expanded Tregs produced significant amounts of TGF-b and IL-10 and depletion of Tregs from PBMC of these individuals increased the frequency of M. tuberculosis-responsive CD4 + IFN-c cells. Culturing M. tuberculosis-expanded Tregs with autologous CD8 + cells decreased the frequency of IFN-c + cells. Freshly isolated PBMC from tuberculosis patients had increased percentages of Tregs, compared to healthy tuberculin reactors. These findings demonstrate that Tregs expand in response to M. tuberculosis through mechanisms that depend on ManLAM and PGE2.

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Section: Increased Percentages Of Tregs In Tuberculosis Patientsmentioning

confidence: 99%

Mannose‐capped lipoarabinomannan‐ and prostaglandin E2‐dependent expansion of regulatory T cells in human Mycobacterium tuberculosis infection

et al. 2008

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“…At the same time, B-cells differentiate into M. tuberculosis-specific antibodysecreting cells. More recently, Th17 cells, secreting interleukin (IL)-17, IL-21 and IL-22, and regulatory T-cells, secreting IL-10 and transforming growth factor-b, have been implicated in coordinating and balancing these primordial driving forces of the cellular immune response [19,20]. These M. tuberculosisspecific effector cells enter the blood circulation and get access to sites of inflammation, such as the lung ( fig.…”

Section: Sectionmentioning

confidence: 99%

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

Mack

Migliori

Sester

et al. 2009

European Respiratory Journal

499

445

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Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-c release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection.In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

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“…First studied in the context of autoimmunity [15], it is now clear that natural Treg play an important role in the control of various pathogens including Leishmania, Mycobacterium tuberculosis and helminths, suppressing pathogen-specific effector T cells in vivo [16][17][18][19]. Considerably less is known about the role of Treg in malaria.…”

Section: Introductionmentioning

confidence: 99%

Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission

et al. 2009

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An important aspect of clinical immunity to malaria is the ability to down-regulate inflammatory responses, once parasitaemia is under control, in order to avoid immunemediated pathology. The role of classical (CD4 CD127lo/À FOXP3 1 ) Treg in this process, however, remains controversial. Thus, we have characterized the frequency, phenotype and function of Treg populations, over time, in healthy individuals in The Gambia. We observed that both the percentage and the absolute number of CD4lo/À T cells were higher among individuals living in a rural village with highly seasonal malaria transmission than among individuals living in an urban area where malaria rarely occurs. These CD4 1 FOXP31 CD127 lo/À T cells exhibited an effector memory and apoptosis-prone phenotype and suppressed cytokine production in response to malaria antigen. Cells from individuals exposed to malaria expressed significantly higher levels of mRNA for forkhead box P3 and T-box 21 (T-BET) at the end of the malaria transmission season than at the end of the non-transmission season. Importantly, the ratio of T-BET to forkhead box P3 was remarkably consistent between populations and over time, indicating that in healthy individuals, a transient increase in Th1 responses during the malaria transmission season is balanced by a commensurate Treg response, ensuring that immune homeostasis is maintained.Key words: Human . Malaria . Regulation . T cells Supporting Information available online IntroductionA strong pro-inflammatory response, characterized by IFN-g and TNF-a, contributes to the initial killing and clearance of malariainfected RBC [1]. However, immune-mediated pathologypredominantly observed in non-immune and semi-immune subjects -has been linked to sustained and/or excessive inflammatory responses in animal malaria models [2] and human disease [3]. Indeed, ratios of inflammatory to regulatory cytokines seem to determine the severity of disease: low levels of and 8] have been associated with acute or severe malaria, and high ratios of IFN-g, TNF-a and IL-12 to TGF-b or IL-10 are associated with decreased risk of malaria infection but increased risk of clinical disease in those who do Ã These authors contributed equally to this work. 1288become infected [9,10]. Moreover, in vitro parasite-induced IFN-g production by PBMC is considerably lower among clinically immune individuals than among semi-immune subjects [11,12]. This has led to the hypothesis that the ability to down-regulate inflammatory responses -once parasitaemia is under control -is crucial to avoid immune-mediated pathology, and may therefore be an important feature of clinical immunity to malaria [3,13].The balance between pro-inflammatory and regulatory immune mechanisms is crucial in determining the outcome of many parasitic infections [13,14]: pro-inflammatory responses, though essential to clear infection, can also lead to severe disease and need to be very tightly regulated in order to maintain immune homeostasis.Treg, first characterised by a high level of CD25 expressi...

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Cutting Edge: Regulatory T Cells Prevent Efficient Clearance of Mycobacterium tuberculosis

Cited by 248 publications

References 25 publications

Mannose‐capped lipoarabinomannan‐ and prostaglandin E2‐dependent expansion of regulatory T cells in human Mycobacterium tuberculosis infection

Mannose‐capped lipoarabinomannan‐ and prostaglandin E2‐dependent expansion of regulatory T cells in human Mycobacterium tuberculosis infection

LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement

Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission

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