Mycobacterium tuberculosis-specific CD4+, IFNγ+, and TNFα+ multifunctional memory T cells coexpress GM-CSF

Mueller, Henrik; Detjen, Anne; Schuck, Sebastian; Gutschmidt, Andrea; Wahn, Ulrich; Magdorf, K.; Kaufmann, Stefan H. E.; Jacobsen, Marc

doi:10.1016/j.cyto.2008.05.002

Cited by 72 publications

(68 citation statements)

References 26 publications

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“…We report here that the Ag85B/TB10.4-specific T-cell response was characterized by an effector memory phenotype. This is in agreement with memory phenotypes reported previously on mycobacteriaspecific T cells in adults (54), children (55), and infants (44,45). Both presence and absence of the differentiation marker, CD27, was observed on these effector memory CD4 and CD8 T cells, suggesting an intermediate to an advanced stage of differentiation.…”

Section: Discussionsupporting

confidence: 80%

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

Tena-Coki¹,

Scriba²,

Peteni³

et al. 2010

Am J Respir Crit Care Med

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Section: Discussionsupporting

confidence: 80%

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

Tena-Coki¹,

Scriba²,

Peteni³

et al. 2010

Am J Respir Crit Care Med

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“…1). Even though this phenomenon had been previously observed in some studies (13,26), it has not been seriously considered. Based on our finding, the ratio of TB antigen-specific to mitogen-induced nonspecific responses was therefore calculated in individual samples (Fig.…”

Section: Ratio Of Tb-specific To Mitogen-induced Responsesmentioning

confidence: 91%

Discrimination between Active and Latent Tuberculosis Based on Ratio of Antigen-Specific to Mitogen-Induced IP-10 Production

et al. 2015

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f Mycobacterium tuberculosis is the major causative agent of tuberculosis (TB). The gamma interferon (IFN-␥) release assay (IGRA) has been widely used to diagnose TB by testing cell-mediated immune responses but has no capacity for distinguishing between active TB and latent TB infection (LTBI). This study aims to identify a parameter that will help to discriminate active TB and LTBI. Whole-blood samples from 33 active TB patients, 20 individuals with LTBI, and 26 non-TB controls were applied to the commercial IFN-␥ release assay, QuantiFERON-TB Gold In-Tube, and plasma samples were analyzed for interleukin-2 (IL-2), IL-6, IL-8, IL-10, IL-13, tumor necrosis factor-alpha (TNF-␣), IFN-␥, monokine induced by IFN-␥ (MIG), interferon gamma inducible protein 10 (IP-10), interferon-inducible T cell alpha chemoattractant (I-TAC), and monocyte chemoattractant protein 1 (MCP-1) by using a commercial cytometric bead array. The Mycobacterium tuberculosis antigen-specific production of most of the assayed cytokines and chemokines was higher in the active TB than in the LTBI group. The mitogen-induced responses were lower in the active TB than in the LTBI group. When the ratio of TB-specific to mitogen-induced responses was calculated, IL-2, IL-6, IL-10, IL-13, TNF-␣, IFN-␥, MIG, and IP-10 were more useful in discriminating active TB from LTBI. In particular, most patients showed higher IP-10 production to Mycobacterium tuberculosis antigens than to mitogen at the individual level, and the ratio for IP-10 was the strongest indicator of active infection versus LTBI with 93.9% sensitivity and 90% specificity. In conclusion, the ratio of the TB-specific to the mitogen-induced IP-10 responses showed the most promising accuracy for discriminating active TB versus LTBI and should be further studied to determine whether it can serve as a biomarker that might help clinicians administer appropriate treatments. M ycobacterium tuberculosis, the major causative agent for tuberculosis (TB), is among the most successful human pathogens, infecting approximately 8.6 million people and leading to 1.3 million deaths each year (1). It is estimated that 2 billion people live with latent TB infection (LTBI) and are therefore a potential source of active TB (2, 3). Identifying LTBI is necessary in order to reduce the risk of development of the disease, while diagnosis of active TB can enable rapid treatment and disease control. To this end, diagnostic biomarkers that can accurately indicate disease status are needed (4, 5).There is presently no diagnostic gold standard for LTBI. Until recently, the tuberculin skin test (TST) involving the intracutaneous injection of purified protein derivative (PPD) into the forearm was the only available method for diagnosing LTBI. However, PPD cross-reacts with nontuberculous mycobacteria as well as with Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine and has poor sensitivity in immunocompromised patients (6). The interferon gamma (IFN-␥) release assay (IGRA) has been widely used in clinical practice a...

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“…Although no direct evidence was provided that these cells actually conferred protection against M. tuberculosis in that study [11], the presence of large numbers of multifunctional T cells in the lungs of mice boosted with a recombinant adenovirus expressing M. tuberculosis Ag85A correlated with a reduction in mycobacterial burden in M. tuberculosis aerosolchallenged animals [12,13]. 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].…”

mentioning

confidence: 99%

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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Mycobacterium tuberculosis-specific CD4+, IFNγ+, and TNFα+ multifunctional memory T cells coexpress GM-CSF

Cited by 72 publications

References 26 publications

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

Discrimination between Active and Latent Tuberculosis Based on Ratio of Antigen-Specific to Mitogen-Induced IP-10 Production

Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection

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Mycobacterium tuberculosis-specific CD4+, IFNγ+, and TNFα+ multifunctional memory T cells coexpress GM-CSF

Cited by 72 publications

References 26 publications

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

CD4 and CD8 T-Cell Responses to Mycobacterial Antigens in African Children

Discrimination between Active and Latent Tuberculosis Based on Ratio of Antigen-Specific to Mitogen-Induced IP-10 Production

Multifunctional CD4+ T cells correlate with active Mycobacterium tuberculosis infection

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Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection