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Abstract
Identifying a blood circulating cellular biomarker that can be used to assess severity of disease and predict the time to culture conversion (TCC) in patients with multidrug resistant tuberculosis (MDR-TB) would facilitate monitoring response to treatment and may be of value in the design of future drug trials. We report on the frequency of blood Ki67+HLA-DR− CD4+ T regulatory (Treg) cells in predicting microbiological outcome before initiating second-line treatment for MDR-TB. Fifty-one patients with MDR-TB were enrolled and followed over 18 months; a subset of patients was sputum culture (SC) negative at baseline (n = 9). SC positive patients were divided into two groups, based on median TCC: rapid responders (≤71 days TCC; n = 21) and slow responders (>71 days TCC; n = 21). Whole blood at baseline, months 2 and 6 was stimulated with M tuberculosis (Mtb) antigens and Treg cells were then identified as CD3+CD4+CD25hiFoxP3+CD127−CD69− and further delineated as Ki67+HLA-DR− Treg. The frequency of these cells was significantly enlarged at baseline in SC positive relative to SC negative and smear positive relative to smear negative patients and in those with lung cavitation. This difference was further supported by unsupervised hierarchical clustering showing a significant grouping at baseline of total and early differentiated memory Treg cells in slow responders. Conversely, there was a clustering of a lower proportion of Treg cells and activated IFNγ-expressing T cells at baseline in the rapid responders. Examining changes over time revealed a more gradual reduction of Treg cells in slow responders relative to rapid responders to treatment. Receiver operating curve analysis showed that baseline Mtb-stimulated Ki67+HLA-DR− Treg cells could predict the TCC of MDR-TB treatment response with 81.2% sensitivity and 85% specificity (AUC of 0.87, p < 0.0001), but this was not the case after 2 months of treatment. In conclusion, our data show that the frequency of a highly defined Mtb-stimulated blood Treg cell population at baseline can discriminate MDR-TB disease severity and predict time to culture clearance.
Highlights
Multidrug resistant tuberculosis (MDR-TB) is a major global concern and none more than in Africa, where the HIV epidemic in numerous countries fuels enhanced TB disease, including the increasing burden of MDR and XDR-TB, and accelerated mortality in these patients [1, 2]
When we examined for the presence of these cells in SC+ patients (n = 42) responding either rapidly or slowly to second line therapy, the frequency of Ki67+HLA-DR− Treg cells significantly distinguished the pace of Mtb clearance (Figure 1G)
To understand whether proliferative-competent Treg cells was a characteristic associated with microbiological outcome, we examined whether non-proliferating Mtbstimulated Ki67−HLA-DR− regulatory T cells could discriminate between responder groups
Summary
Multidrug resistant tuberculosis (MDR-TB) is a major global concern and none more than in Africa, where the HIV epidemic in numerous countries fuels enhanced TB disease, including the increasing burden of MDR and XDR-TB, and accelerated mortality in these patients [1, 2]. Circulating regulatory CD4+CD25+FoxP3+ T cells (Treg) are involved in the regulation of self-tolerance, autoimmunity, and suppression of immune responses during infections [4] These cells are increased in both drug-sensitive- and MDR-TB, where they are associated with high bacillary burden [5,6,7] and are possibly induced by chronic inflammation [8]. The suppression of potentially protective anti-TB immunity and the short-range action of these soluble suppressive mediators could result in unchecked bacterial replication and renders the host to unregulated inflammation and the spread of pathology This is a seemingly counter-intuitive involvement of Treg cells in TB pathology. We wished to include actively proliferating cells by focusing on Ki67-expression [23] and our defined Treg subset, CD3+CD4+CD25hiFoxP3+CD127−CD69−Ki67+HLADR−, was able to discriminate between sputum culture (SC) negative and positive and those with and without lung cavitation. The presence of these proliferating Tregs, in response to whole blood Mtb antigen re-stimulation, could predict the time to culture conversion (TCC) and serve as a marker of microbiological outcome
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