Detection of Polyfunctional<i>Mycobacterium tuberculosis</i>–Specific T Cells and Association with Viral Load in HIV‐1–Infected Persons

Day, Cheryl L.; Mkhwanazi, Nompumelelo; Reddy, Shabashini; Mncube, Zenele; Stok, Mary van der; Klenerman, Paul; Walker, Bruce D.

doi:10.1086/529048

Cited by 110 publications

(93 citation statements)

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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].…”

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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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Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection

et al. 2010

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“…A negative correlation was found between HIV-viral load and the proportion of MTB-specific IL-2-secreting (IFN-g 1 /IL-2 1 and IFN-g/IL-2 1 ) CD4 1 T cells and a positive correlation was found with IFN-g single positive CD4 1 T cells and HIV-1 viral load [14]. These data suggest that MTB-specific T cells secreting IL-2 (with or without IFN-g) may be proportionally diminished when HIV-1 viral load is high, corresponding with greater susceptibility to develop active TB.…”

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confidence: 89%

Polyfunctional T cells in human tuberculosis

Wilkinson

2010

Eur J Immunol

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Studies of chronic viral infections have highlighted the phenotypic and functional heterogeneity of antigen-specific T cells and suggested that polyfunctional T cells that secrete multiple cytokines and are able to proliferate on encounter with antigen are more likely than single cytokine secretors to represent correlates of protective immunity. These findings have prompted the evaluation of such T-cell responses in chronic bacterial infections, such as tuberculosis (TB). A number of studies in humans suggested that polyfunctional T cells may indeed be involved in mediating protection in TB; however, studies that question these findings are also emerging, including a study published in this issue of the European Journal of Immunology. These differing findings highlight the difficulties of studying human immunity to TB and the need for polyfunctional T cells to be evaluated in longitudinal studies as opposed to case-control analyses.

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“…Children with deficiencies in the IL-12 or IFN-␥ pathways are known to be susceptible to disseminated disease (17,29,32). Further, polyfunctional T cells have been associated with resistance to infection in animal models, although human data are still scarce (9,12,27). In contrast, a number of regulatory factors, including regulatory T cells (Tregs), IL-10, transforming growth factor ␤ (TGF-␤), cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), and programmed death 1 (PD-1) have been implicated in establishment of chronic M. tuberculosis infection by downmodulating protective immune responses (2,14,19,33,39).…”

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Suppressed Type 1, Type 2, and Type 17 Cytokine Responses in Active Tuberculosis in Children

Kumar

Ray

Suresh

et al. 2011

Clin Vaccine Immunol

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Detection of PolyfunctionalMycobacterium tuberculosis–Specific T Cells and Association with Viral Load in HIV‐1–Infected Persons

Abstract: Polyfunctional MTB-specific CD4 and CD8 T cell responses are maintained in the peripheral blood of HIV-1-positive individuals, in the absence of active disease, and the functional capacity of these responses is affected by HIV-1 disease status.

Cited by 110 publications

References 49 publications

Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection

Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection

Polyfunctional T cells in human tuberculosis

Suppressed Type 1, Type 2, and Type 17 Cytokine Responses in Active Tuberculosis in Children

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Detection of PolyfunctionalMycobacterium tuberculosis–Specific T Cells and Association with Viral Load in HIV‐1–Infected Persons

Abstract: Polyfunctional MTB-specific CD4 and CD8 T cell responses are maintained in the peripheral blood of HIV-1-positive individuals, in the absence of active disease, and the functional capacity of these responses is affected by HIV-1 disease status.

Cited by 110 publications

References 49 publications

Multifunctional CD4+ T cells correlate with active Mycobacterium tuberculosis infection

Multifunctional CD4+ T cells correlate with active Mycobacterium tuberculosis infection

Polyfunctional T cells in human tuberculosis

Suppressed Type 1, Type 2, and Type 17 Cytokine Responses in Active Tuberculosis in Children

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Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection

Multifunctional CD4⁺ T cells correlate with active Mycobacterium tuberculosis infection