Mtb-Specific CD27low CD4 T Cells as Markers of Lung Tissue Destruction during Pulmonary Tuberculosis in Humans

Abstract

BackgroundEffector CD4 T cells represent a key component of the host’s anti-tuberculosis immune defense. Successful differentiation and functioning of effector lymphocytes protects the host against severe M. tuberculosis (Mtb) infection. On the other hand, effector T cell differentiation depends on disease severity/activity, as T cell responses are driven by antigenic and inflammatory stimuli released during infection. Thus, tuberculosis (TB) progression and the degree of effector CD4 T cell differentiation are interrelated, but the relationships are complex and not well understood. We have analyzed an association between the degree of Mtb-specific CD4 T cell differentiation and severity/activity of pulmonary TB infection.Methodology/Principal FindingsThe degree of CD4 T cell differentiation was assessed by measuring the percentages of highly differentiated CD27low cells within a population of Mtb- specific CD4 T lymphocytes (“CD27lowIFN-γ+” cells). The percentages of CD27lowIFN-γ+ cells were low in healthy donors (median, 33.1%) and TB contacts (21.8%) but increased in TB patients (47.3%, p<0.0005). Within the group of patients, the percentages of CD27lowIFN-γ+ cells were uniformly high in the lungs (>76%), but varied in blood (12–92%). The major correlate for the accumulation of CD27lowIFN-γ+ cells in blood was lung destruction (r = 0.65, p = 2.7×10−7). A cutoff of 47% of CD27lowIFN-γ+ cells discriminated patients with high and low degree of lung destruction (sensitivity 89%, specificity 74%); a decline in CD27lowIFN-γ+cells following TB therapy correlated with repair and/or reduction of lung destruction (p<0.01).ConclusionsHighly differentiated CD27low Mtb-specific (CD27lowIFN-γ+) CD4 T cells accumulate in the lungs and circulate in the blood of patients with active pulmonary TB. Accumulation of CD27lowIFN-γ+ cells in the blood is associated with lung destruction. The findings indicate that there is no deficiency in CD4 T cell differentiation during TB; evaluation of CD27lowIFN-γ+ cells provides a valuable means to assess TB activity, lung destruction, and tissue repair following TB therapy.

Assessment of CD27 expression as a tool for active and latent tuberculosis diagnosis

“…46 Interestingly, CD4 þ T-cells with a low CD27 surface expression have also been described as a marker of lung tissue destruction during pulmonary TB, suggesting its use as an immune assay to monitor the efficacy of TB therapy. 38 The studies on CD27 expression on Mtb-specific T-cells show similar and reproducible results, despite the differences of the experimental settings and clinical characteristics of the enrolled patients. 22,38e43,47 Therefore, the phenotype data of the CD4 þ T-cells are more consistent compared to the cytokine profile studies, suggesting that CD27 evaluation on Mtb specific-CD4 þ T-cells may be a useful tool for diagnosing TB stages.…”

“…53 Therefore, the decrease of CD27 expression on CD4 þ Tcells indicates the presence of highly differentiated effector T-cells that are able to produce cytokines. 38,44,45,54 TB is a chronic disease that leads to the increase of terminally differentiated T-cells. 14,22,43,55 In the present study, we show that one year after completion of TB therapy the level of CD27 expression increases in cured TB patients, indicating that the lack of a sustained inflammation leads the T-cells toward a less differentiated phenotype, probably with memory features.…”

“…Our data are supported by the finding that 2 months of TB therapy are enough to observe a lower proportion of CD27 low CD4 þ IFN-g þ T-cells. 38 This evidence suggests that CD27 may also be a useful tool for monitoring TB therapy efficacy.…”

Measurement of Phenotype and Absolute Number of Circulating Heparin-Binding Hemagglutinin, ESAT-6 and CFP-10, and Purified Protein Derivative Antigen-Specific CD4 T Cells Can Discriminate Active from Latent Tuberculosis Infection

“…In particular, we found that the changes in HBHA-specific CD4 T cell frequencies were mirrored by changes in absolute numbers, which was not the case for the PPD-specific and the ESAT-6-and CFP-10-specific cells. Others have reported no differences in absolute numbers of Mycobacterium bovis BCG-spe- cific CD4 T cells in patients with TB infection versus healthy, skin test-positive controls (7) or of sonicated M. tuberculosis-specific CD4 T cells from actively infected individuals and M. tuberculosisexposed healthy controls (25). Why there is a difference in absolute numbers for HBHA stimulation but not with the other antigens is an interesting question, with the higher concentration of HBHA-specific CD4 T cells perhaps indicating that they are part of an ongoing systemic response in the latently infected population.…”

Impact of Hiv Infection and Tuberculosis on the Peripheral Blood T-Cell Differentiation

“…Этот показатель характеризует функциональную активность эф-фекторных Т-клеток и позволяет оценить тяжесть (активность) инфекционного процесса. Диффе-ренцировка T-лимфоцитов при ВИЧ-инфекции [9,17] и туберкулезе [12,16] как моноинфекций изучена достаточно подробно, в то время как ис-следования синергичного взаимодействие ВИЧ и туберкулеза на дифференцировку клеток не-многочисленны и нередко противоречивы.…”