Increased specific T cell cytokine responses in patients with active pulmonary tuberculosis from Central Africa

Winkler, Stefan; Necek, Magdalena; Winkler, Heidi; Adegnika, Ayôla Akim; Perkmann, Thomas; Ramharter, Michael; Kremsner, Peter G.

doi:10.1016/j.micinf.2005.03.020

Cited by 36 publications

(34 citation statements)

References 59 publications

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“…Because we asked patients to return more than 4 months after the anthelmintic treatment, we do not think the treatment itself has a direct impact on the frequency of Figure 6, the control unstimulated PBMC cultures also showed higher CD4 + IFN-γ + T-cell frequencies in the FoxP3-depleted fractions than in the nondepleted cultures. Furthermore, some studies suggest that intracellular IFN-γ does not correlate with protection against Mtb infection [41,42], although the measurement of IFN-γ is still a relevant marker of the immune response [7,43,44].…”

Section: Discussionmentioning

confidence: 99%

“…It is important to note that in our cohort we did not observe any difference in the frequency of CD4 + FoxP3 + T cells between the control and the LTBI Figure 6, the control unstimulated PBMC cultures also showed higher CD4 + IFN-γ + T-cell frequencies in the FoxP3-depleted fractions than in the nondepleted cultures. Furthermore, some studies suggest that intracellular IFN-γ does not correlate with protection against Mtb infection [41,42], although the measurement of IFN-γ is still a relevant marker of the immune response [7,43,44].Tregs are thought to exert their function via a number of different mechanisms including IL-10 and/or TGF-β production, IL-2 consumption, or cell-cell contact where inhibitory molecules such as CTLA-4 and PD-1 are key [45,46]. In a study on the impact of FoxP3 T cells in the modulation of immune responses …”

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Mycobacterium tuberculosis‐specific CD4⁺ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

et al. 2016

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In many settings, adults with active or latent tuberculosis will also be coinfected with helminths. Our study aimed to investigate how anthelmintic treatment modulates antimycobacterial immunity, in a setting where helminth reinfection should not occur. Additional supporting information may be found in the online version of this article at the publisher's web-site We investigated the potential impact of helminth infection on immune responses to Mycobacterium tuberculosis (Mtb) in patients with latent Mtb infection with or without helminth infection (Strongyloides orSchistosoma IntroductionMycobacterium tuberculosis (Mtb) infects a third of the world's population, causing 1.5 million deaths a year [1,2]. In addi- Correspondence:Frederic Toulza e-mail: Frederic.Toulza@lshtm.ac.uk tion, helminth infections are estimated to affect 1.5 billion people worldwide, with the majority of these infections concentrated in developing countries where tuberculosis (TB) is endemic [3,4]. Helminth infections are reported to induce Th2 type immune responses in the host [5], and evidence suggests that Th2 cytokines may play a critical role in reducing the Th1 immune response to other infections. Protection against TB is not well understood, but Th1 T-cell responses involving interferon gamma (IFN-γ), tumor C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 752-761 Clinical immunology 753 necrosis factor alpha (TNF-α), and interleukin 2 (IL-2) are induced in the immune response to Mtb [6]. IFN-γ is thought to play an important role in the protective immune response against TB as indicated by the susceptibility of humans with IFN-γ signaling pathway deficiencies to TB disease [7,8]. A number of studies have previously investigated the immunomodulatory effect of helminth infection on antimycobacterial immunity (reviewed in [9] [22,23] and in patients with active TB [24]. A recent study showed that in children in Gabon, the proportion of Tregs decreased with anthelmintic treatment [25].There have been only a few studies that investigated the impact of helminth infections on T-cell immunity in patients with latent TB infection. Filaria infections were shown to reduce Th1 responses in Indian patients with latent Mtb infection (LTBI), that were increased with blockage of CTLA-4 or PD-1 [26], while anthelminth treatment increased TLR2 and TLR9 expression with an associated increase in production of proinflammatory cytokines. In Indian patients with LTBI, coincident hookworm infection reduced Mtb-specific Th1 and Th17 CD4 T cells [14]. Indian pulmonary TB patients with Wucheria or Stronglyoides also showed reduced CD4 and CD8 T-cell responses to mycobacterial antigens, which could be partly blocked with anti-IL-10 neutralizing antibodies [27].In this study, we measured the impact of anthelmintic treatment on the immune response to Mtb in LTBI in a migrant cohort in London. As United Kingdom is not a helminth endemic area, reinfection is not likely in this setting. This provides a unique opport...

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Mycobacterium tuberculosis‐specific CD4⁺ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

et al. 2016

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“…Although systemic production of IFN-␥ by M. tuberculosis-stimulated peripheral blood mononuclear cells (PBMC) from patients with moderate and far-advanced pulmonary TB is depressed, the local immune response shows an increased frequency of IFN-␥-producing cells. Indeed, patients with active disease may have higher levels of IFN-␥ in plasma and in sputum, suggesting that the levels of this cytokine are a reflection of the intensity of immunopathology and bacterial load in the lungs rather than evidence of a protective response (14)(15)(16). It seems likely that IFN-␥ production is necessary but insufficient for protection and in the setting of concomitant M. tuberculosis disease may contribute to pathogenesis.…”

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Quest for Correlates of Protection against Tuberculosis

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et al. 2015

Clin. Vaccine Immunol.

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A major impediment to tuberculosis (TB) vaccine development is the lack of reliable correlates of immune protection or biomarkers that would predict vaccine efficacy. Gamma interferon (IFN-␥) produced by CD4 ؉ T cells and, recently, multifunctional CD4 ؉ T cells secreting IFN-␥, tumor necrosis factor (TNF), and interleukin-2 (IL-2) have been used in vaccine studies as a measurable immune parameter, reflecting activity of a vaccine and potentially predicting protection. However, accumulating experimental evidence suggests that host resistance against Mycobacterium tuberculosis infection is independent of IFN-␥ and TNF secretion from CD4 ؉ T cells. Furthermore, the booster vaccine MVA85A, despite generating a high level of multifunctional CD4؉ T cell response in the host, failed to confer enhanced protection in vaccinated subjects. These findings suggest the need for identifying reliable correlates of protection to determine the efficacy of TB vaccine candidates. This article focuses on alternative pathways that mediate M. tuberculosis control and their potential for serving as markers of protection. The review also discusses the significance of investigating the natural human immune response to M. tuberculosis to identify the correlates of protection in vaccination.

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“…Multifunctional M. tuberculosisspecific CD4 1 T cells have been detected in peripheral blood of children with active TB disease and children with LTBI [14], and are maintained in HIV-1-positive individuals in the absence of active disease [15], although their functional capacity is affected by HIV-1 disease status both in peripheral blood [15] and in the lungs [16]. Moreover, it has been suggested that combined analyses of different cytokines coexpressed by multifunctional T cells can improve discrimination between TB patients and subjects with LTBI [17,18]. Therefore, quality rather than quantity of M. tuberculosis-specific T-cell responses has been assumed to indicate protection and the capacity to generate longterm memory.…”

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Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection

et al. 2010

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Th1 CD41 T cells and their derived cytokines are crucial for protection against Mycobacterium tuberculosis. Using multiparametric flow cytometry, we have evaluated the distribution of seven distinct functional states (IFN-c/IL-2/TNF-a triple expressors, IFN-c/IL-2, IFN-c/TNF-a or TNF-a/IL-2 double expressors or IFN-c, IL-2 or TNF-a single expressors) of CD4 1 T cells in individuals with latent M. tuberculosis infection (LTBI) and active tuberculosis (TB). We found that triple expressors, while detectable in 85-90%TB patients, were only present in 10-15% of LTBI subjects. On the contrary, LTBI subjects had significantly higher (12-to 15-fold) proportions of IL-2/IFN-c double and IFN-c single expressors as compared with the other CD4 1 T-cell subsets. Proportions of the other double or single CD4 1 T-cell expressors did not differ between TB and LTBI subjects. These distinct IFN-c, IL-2 and TNF-a profiles of M. tuberculosis-specific CD4 1 T cells seem to be associated with live bacterial loads, as indicated by the decrease in frequency of multifunctional T cells in TB-infected patients after completion of anti-mycobacterial therapy. Our results suggest that phenotypic and functional signatures of CD4 1 T cells may serve as immunological correlates of protection and curative host responses, and be a useful tool to monitor the efficacy of anti-mycobacterial therapy. IntroductionInfections with Mycobacterium tuberculosis (M. tuberculosis) cause a global epidemic with almost 9 million new cases and over 1.6 million deaths per year [1,2]. Outcome of M. tuberculosis infection depends on early identification and proper treatment of individuals with active tuberculosis (TB), but the lack of accurate diagnostic techniques has contributed to the re-emergence of TB as a global health threat. More than 2 billion individuals are estimated to be latently infected with M. tuberculosis (LTBI). To date, however, Ã These authors have contributed equally to this work. There were a number of differences between TB patients and subjects with LTBI following stimulation with ESAT-6, Ag85B and the 16-kDa antigen (Fig. 2). Most notably, and in contrast with the previously reported results in chronic viral infections, we found a significantly higher proportion of 31 CD4 1 T cells simultaneously secreting IFN-g, IL-2 and TNF-a in patients with TB, as compared with LTBI subjects, upon stimulation with any of the three tested M. tuberculosis antigens (Fig. 2). Using a threshold of 0.01% to avoid systematic biases incurred by zeroing negative values (frequency values o0.01% were set to zero), we found that 31 CD4 1 T cells were detectable in very few LTBI subjects (3/18, 3/18 and 2/18 in response to Ag85B, ESAT-6 and 16 kDa, respectively), but were frequently detected in most TB patients (17/20, 18/20 and 17/20, in Eur. J. Immunol. 2010. 40: 2211-2220 Nadia Caccamo et al. 2212& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu response to Ag85B, ESAT-6 and 16 kDa, respectively; see also Table 1 for comparison).In contrast, ...

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Increased specific T cell cytokine responses in patients with active pulmonary tuberculosis from Central Africa

Cited by 36 publications

References 59 publications

Mycobacterium tuberculosis‐specific CD4⁺ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

Mycobacterium tuberculosis‐specific CD4⁺ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

Quest for Correlates of Protection against Tuberculosis

Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection

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Increased specific T cell cytokine responses in patients with active pulmonary tuberculosis from Central Africa

Cited by 36 publications

References 59 publications

Mycobacterium tuberculosis‐specific CD4+ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

Mycobacterium tuberculosis‐specific CD4+ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

Quest for Correlates of Protection against Tuberculosis

Multifunctional CD4+ T cells correlate with active Mycobacterium tuberculosis infection

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Mycobacterium tuberculosis‐specific CD4⁺ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

Mycobacterium tuberculosis‐specific CD4⁺ T‐cell response is increased, and Treg cells decreased, in anthelmintic‐treated patients with latent TB

Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection